Methods and compositions for the specific inhibition of transthyretin (TTR) by double stranded RNA

ABSTRACT

This invention relates to compounds, compositions, and methods useful for reducing transth:yretin (TTR) target RNA and protein levels via use of dsRNAs, e.g., Dicer substrate siRNA (DsiRNA) agents.

RELATED APPLICATIONS

The present application is a continuation of U.S. patent applicationSer. No. 16/168,671, filed Oct. 23, 2018, which is a continuation ofU.S. patent application Ser. No. 15/102,181, filed Jun. 6, 2016, whichis a national stage filing under U.S.C. 371 of PCT InternationalApplication No. PCT/US2014/068764, filed Dec. 5, 2014, which claimspriority to, and the benefit under 35 U.S.C. § 119(e) of U.S.provisional patent application No. 61/912,891, entitled “Methods andCompositions for the Specific Inhibition of Transthyretin (TTR) byDouble-Stranded RNA,” filed Dec. 6, 2013. The entire contents of eachapplication are incorporated herein by reference in their entireties.

FIELD OF THE INVENTION

The present invention relates to compounds, compositions, and methodsfor the study, diagnosis, and treatment of traits, diseases andconditions that respond to the modulation of transthyretin geneexpression and/or activity.

SEQUENCE SUBMISSION

The present application is being filed along with a Sequence Listing inelectronic format. The Sequence Listing is entitled “Dicerna_173037_SL”,created on Apr. 1, 2020 and is 686 kb in size. The information in theelectronic format of the Sequence Listing is part of the presentapplication and is incorporated herein by reference in its entirety.

BACKGROUND OF THE INVENTION

Transthyretin (TTR, for “transports thyroxine and retinol” andoriginally named “prealbumin”) is a serum and cerebrospinal fluidcarrier of the thyroid hormone thyroxine (T4) and retinol bindingprotein bound to retinol. The liver secretes transthyretin into theblood, while the choroid plexus secretes TTR into the cerebrospinalfluid. It functions with two other thyroid hormone-binding proteins inthe serum, thyroxine-binding globin (TBG) and albumin.

TTR is a 55 kDa homotetramer with a dimer of dimers quaternary structurethat is synthesized in the liver, choroid plexus and retinal pigmentepithelium for secretion into the bloodstream, cerebrospinal fluid andthe eye, respectively. TTR misfolding and aggregation is known to beassociated with the amyloid diseases (Zeldenrust and Benson. InRamirez-Alvarado M, Kelly J W, Dobson C. Protein misfolding diseases:current and emerging principles and therapies. New York: Wiley) senilesystemic amyloidosis (SSA; Westermark et al. Proc. Natl. Acad. Sci.U.S.A. 87: 2843-5), familial amyloid polyneuropathy (FAP; Andrade C.Brain 75: 408-27; Coelho T. Curr. Opin. Neurol. 9: 355-9), and familialamyloid cardiomyopathy (FAC; Jacobson et al. N. Engl. J. Med. 336:466-73).

TTR tetramer dissociation is known to be rate-limiting for amyloidfibril formation (Colon and Kelly. Biochemistry 31: 8654-60; Lai et al.Biochemistry 35: 6470-82; Hammarstrom et al. Science 299: 713-6).However, the monomer also must partially denature in order for TTR to bemis-assembly competent, leading to a variety of aggregate structuresincluding amyloid fibrils (Jiang et al. Biochemistry 40: 11442-52).While wild type TTR can dissociate, misfold and aggregate leading toSSA, point mutations within TTR are known to destabilize the tetramercomposed of mutant and wild type TTR subunits facilitating more faciledissociation and/or misfolding and amyloidogenesis (Sekijima et al. Cell121 (1): 73-85). A replacement of valine by methionine at position 30(TTR V30M) is the mutation most commonly associated with FAP (Saraiva MJ. Hum. Mutat. 5: 191-6). A position 122 replacement of valine byisoleucine (TTR V1221) is carried by 3.9% of the African-Americanpopulation, and is the most common cause of FAC (Jacobson et al. N.Engl. J. Med. 336: 466-73). SSA is estimated to affect over 25% of thepopulation over age 80 (Westermark et al. Proc. Natl. Acad. Sci. U.S.A.87: 2843-5). Severity of disease varies greatly by mutation, with somemutations causing disease in the first or second decade of life, andothers being more benign. Deposition of TTR amyloid is generallyobserved extracellularly, although TTR deposits are also clearlyobserved within the cardiomyocytes of the heart.

Both normal-sequence TTR and variant-sequence TTR cause amyloidosis.Normal-sequence TTR causes cardiac amyloidosis in people who are elderlyand is termed senile systemic amyloidosis (SSA) (also called senilecardiac amyloidosis (SCA)). SSA often is accompanied by microscopicdeposits in many other organs. TTR mutations accelerate the process ofTTR amyloid formation and are the most important risk factor for thedevelopment of clinically significant TTR amyloidosis (also called ATTR(amyloidosis-transthyretin type)). More than 85 amyloidogenic TTRvariants are known to cause systemic familial amyloidosis. The liver isthe major site of TTR expression. Other significant sites of expressioninclude the choroid plexus, retina and pancreas. TTR amyloidosismanifests in various forms. When the peripheral nervous system isaffected more prominently, the disease is termed familial amyloidoticpolyneuropathy (FAP). When the heart is primarily involved but thenervous system is not, the disease is called familial amyloidoticcardiomyopathy (FAC). A third major type of TTR amyloidosis is calledleptomeningeal/CNS (Central Nervous System) amyloidosis.

Treatment of familial TTR amyloid disease has historically relied onliver transplantation as a crude form of gene therapy (Holmgren et al.Lancet 341: 1113-6). Inhibitory RNA therapies offer the prospect of atargeted and significantly less invasive alternative to such transplanttherapy.

Double-stranded RNA (dsRNA) agents possessing strand lengths of 25 to 35nucleotides have been described as effective inhibitors of target geneexpression in mammalian cells (Rossi et al., U.S. Patent ApplicationNos. 2005/0244858 and US 2005/0277610). dsRNA agents of such length arebelieved to be processed by the Dicer enzyme of the RNA interference(RNAi) pathway, leading such agents to be termed “Dicer substrate siRNA”(“DsiRNA”) agents. Additional modified structures of DsiRNA agents werepreviously described (Rossi et al., U.S. Patent Application No.2007/0265220). Effective extended forms of Dicer substrates have alsorecently been described (see, e.g., Brown, U.S. Pat. Nos. 8,349,809 and8,513,207).

Provided herein are improved nucleic acid agents that targettransthyretin. In particular, those targeting transthyretin have beenspecifically exemplified.

BRIEF SUMMARY OF THE INVENTION

The present invention is directed to nucleic acid compositions thatreduce expression of transthyretin. Such compositions contain nucleicacids such as double stranded RNA (“dsRNA”), and methods for preparingthem. The nucleic acids of the invention are capable of reducing theexpression of a target transthyretin gene in a cell, either in vitro orin a mammalian subject.

In one aspect, the invention provides a nucleic acid possessing anoligonucleotide strand of 15-53 nucleotides in length, where theoligonucleotide strand is sufficiently complementary to a targettransthyretin mRNA sequence of SEQ ID NOs: 1921-2304 along at least 15nucleotides of the oligonucleotide strand length to reduce transthyretintarget mRNA expression when the nucleic acid is introduced into amammalian cell.

Another aspect of the invention provides a nucleic acid possessing anoligonucleotide strand of 19-53 nucleotides in length, where theoligonucleotide strand is sufficiently complementary to a targettransthyretin mRNA sequence of SEQ ID NOs: 1921-2304 along at least 19nucleotides of the oligonucleotide strand length to reduce transthyretintarget mRNA expression when the nucleic acid is introduced into amammalian cell.

In one embodiment, the oligonucleotide strand is 19-35 nucleotides inlength.

An additional aspect of the invention provides a double stranded nucleicacid (dsNA) possessing first and second nucleic acid strands includingRNA, where the first strand is 15-66 nucleotides in length and thesecond strand of the dsNA is 19-66 nucleotides in length, where thesecond oligonucleotide strand is sufficiently complementary to a targettransthyretin mRNA sequence of SEQ ID NOs: 1921-2304 along at least 15nucleotides of the second oligonucleotide strand length to reducetransthyretin target mRNA expression when the double stranded nucleicacid is introduced into a mammalian cell.

Another aspect of the invention provides a double stranded nucleic acid(dsNA) possessing first and second nucleic acid strands, where the firststrand is 15-66 nucleotides in length and the second strand of the dsNAis 19-66 nucleotides in length, where the second oligonucleotide strandis sufficiently complementary to a target transthyretin mRNA sequence ofSEQ ID NOs: 1921-2304 along at least 19 nucleotides of the secondoligonucleotide strand length to reduce transthyretin target mRNAexpression when the double stranded nucleic acid is introduced into amammalian cell.

A further aspect of the invention provides a double stranded nucleicacid (dsNA) possessing first and second nucleic acid strands, where thefirst strand is 15-66 nucleotides in length and the second strand of thedsNA is 19-66 nucleotides in length, where the second oligonucleotidestrand is sufficiently complementary to a target transthyretin mRNAsequence of SEQ ID NOs: 1921-2304 along at least 19 nucleotides of thesecond oligonucleotide strand length to reduce transthyretin target mRNAexpression, and where, starting from the 5′ end of the transthyretinmRNA sequence of SEQ ID NOs: 1921-2304 (position 1), mammalian Ago2cleaves the mRNA at a site between positions 9 and 10 of the sequence,when the double stranded nucleic acid is introduced into a mammaliancell.

Another aspect of the invention provides a dsNA molecule, consisting of:(a) a sense region and an antisense region, where the sense region andthe antisense region together form a duplex region consisting of 25-66base pairs and the antisense region includes a sequence that is thecomplement of a sequence of SEQ ID NOs: 1921-2304; and (b) from zero totwo 3′ overhang regions, where each overhang region is six or fewernucleotides in length, and where, starting from the 5′ end of thetransthyretin mRNA sequence of SEQ ID NOs: 1921-2304 (position 1),mammalian Ago2 cleaves the mRNA at a site between positions 9 and 10 ofthe sequence, when the double stranded nucleic acid is introduced into amammalian cell.

An additional aspect of the invention provides a double stranded nucleicacid (dsNA) possessing first and second nucleic acid strands and aduplex region of at least 25 base pairs, where the first strand is 25-65nucleotides in length and the second strand of the dsNA is 26-66nucleotides in length and includes 1-5 single-stranded nucleotides atits 3′ terminus, where the second oligonucleotide strand is sufficientlycomplementary to a target transthyretin mRNA sequence of SEQ ID NOs:1921-2304 along at least 19 nucleotides of the second oligonucleotidestrand length to reduce transthyretin target gene expression when thedouble stranded nucleic acid is introduced into a mammalian cell.

Another aspect of the invention provides a double stranded nucleic acid(dsNA) possessing first and second nucleic acid strands and a duplexregion of at least 25 base pairs, where the first strand is 25-65nucleotides in length and the second strand of the dsNA is 26-66nucleotides in length and includes 1-5 single-stranded nucleotides atits 3′ terminus, where the 3′ terminus of the first oligonucleotidestrand and the 5′ terminus of the second oligonucleotide strand form ablunt end, and the second oligonucleotide strand is sufficientlycomplementary to a target transthyretin sequence of SEQ ID NOs:1921-2304 along at least 19 nucleotides of the second oligonucleotidestrand length to reduce transthyretin mRNA expression when the doublestranded nucleic acid is introduced into a mammalian cell.

In one embodiment, the first strand is 15-35 nucleotides in length.

In another embodiment, the second strand is 19-35 nucleotides in length.

In an additional embodiment, the dsNA possesses a duplex region of atleast 25 base pairs; 19-21 base pairs or 21-25 base pairs.

Optionally, the second oligonucleotide strand includes 1-5single-stranded nucleotides at its 3′ terminus.

In one embodiment, the second oligonucleotide strand includes 5-35single-stranded nucleotides at its 3′ terminus.

In another embodiment, the single-stranded nucleotides include modifiednucleotides. Optionally, the single-stranded nucleotides include2′-O-methyl, 2′-methoxyethoxy, 2′-fluoro, 2′-allyl,2′-O-[2-(methylamino)-2-oxoethyl], 4′-thio, 4′-CH2-O-2′-bridge,4′-(CH2)2-O-2′-bridge, 2′-LNA, 2′-amino and/or 2′-O—(N-methlycarbamate)modified nucleotides.

In certain embodiments, the single-stranded nucleotides includeribonucleotides.

Optionally, the single-stranded nucleotides includedeoxyribonucleotides.

In certain embodiments, the 3′ end of the first strand and the 5′ end ofthe second strand of a dsNA or hybridization complex of the inventionare joined by a polynucleotide sequence that includes ribonucleotides,deoxyribonucleotides or both, optionally the polynucleotide sequenceincludes a tetraloop sequence.

In one embodiment, the first strand is 25-35 nucleotides in length.Optionally, the second strand is 25-35 nucleotides in length.

In one embodiment, the second oligonucleotide strand is complementary totarget transthyretin cDNA sequence GenBank Accession No. NM_000371.3along at most 27 nucleotides of the second oligonucleotide strandlength.

In another embodiment, starting from the first nucleotide (position 1)at the 3′ terminus of the first oligonucleotide strand, position 1, 2and/or 3 is substituted with a modified nucleotide.

Optionally, the first strand and the 5′ terminus of the second strandform a blunt end.

In one embodiment, the first strand is 25 nucleotides in length and thesecond strand is 27 nucleotides in length.

In another embodiment, starting from the 5′ end of a transthyretin mRNAsequence of SEQ ID NOs: 1921-2304 (position 1), mammalian Ago2 cleavesthe mRNA at a site between positions 9 and 10 of the sequence, therebyreducing transthyretin target mRNA expression when the double strandednucleic acid is introduced into a mammalian cell.

In one embodiment, the second strand includes a sequence of SEQ ID NOs:385-768.

In an additional embodiment, the first strand includes a sequence of SEQID NOs: 1-384.

In another embodiment, the dsNA of the invention possesses a pair offirst strand/second strand sequences of Table 2.

Optionally, the modified nucleotide residue of the 3′ terminus of thefirst strand is a deoxyribonucleotide, an acyclonucleotide or afluorescent molecule.

In one embodiment, position 1 of the 3′ terminus of the firstoligonucleotide strand is a deoxyribonucleotide.

In another embodiment, the nucleotides of the 1-5 or 5-35single-stranded nucleotides of the 3′ terminus of the second strandcomprise a modified nucleotide.

In one embodiment, the modified nucleotide of the 1-5 or 5-35single-stranded nucleotides of the 3′ terminus of the second strand is a2′-O-methyl ribonucleotide.

In an additional embodiment, all nucleotides of the 1-5 or 5-35single-stranded nucleotides of the 3′ terminus of the second strand aremodified nucleotides.

In another embodiment, the dsNA includes a modified nucleotide.Optionally, the modified nucleotide residue is 2′-O-methyl,2′-methoxyethoxy, 2′-fluoro, 2′-allyl,2′-O-[2-(methylamino)-2-oxoethyl], 4′-thio, 4′-CH2-O-2′-bridge,4′-(CH2)2-O-2′-bridge, 2′-LNA, 2′-amino or 2′-O—(N-methlycarbamate).

In one embodiment, the 1-5 or 5-35 single-stranded nucleotides of the 3′terminus of the second strand are 1-3 nucleotides in length, optionally1-2 nucleotides in length.

In another embodiment, the 1-5 or 5-35 single-stranded nucleotides ofthe 3′ terminus of the second strand is two nucleotides in length andincludes a 2′-O-methyl modified ribonucleotide.

In one embodiment, the second oligonucleotide strand includes amodification pattern of AS-M1 to AS-M96 and AS-M1* to AS-M96*.

In another embodiment, the first oligonucleotide strand includes amodification pattern of SM1 to SM119.

In an additional embodiment, each of the first and the second strandshas a length which is at least 26 and at most 30 nucleotides.

In one embodiment, the dsNA is cleaved endogenously in the cell byDicer.

In another embodiment, the amount of the nucleic acid sufficient toreduce expression of the target gene is of 1 nanomolar or less, 200picomolar or less, 100 picomolar or less, 50 picomolar or less, 20picomolar or less, 10 picomolar or less, 5 picomolar or less, 2,picomolar or less and 1 picomolar or less in the environment of thecell.

In one embodiment, the dsNA possesses greater potency than a 21 mersiRNA directed to the identical at least 19 nucleotides of the targettransthyretin mRNA in reducing target transthyretin mRNA expression whenassayed in vitro in a mammalian cell at an effective concentration inthe environment of a cell of 1 nanomolar or less.

In an additional embodiment, the nucleic acid or dsNA is sufficientlycomplementary to the target transthyretin mRNA sequence to reducetransthyretin target mRNA expression by an amount (expressed by %) of atleast 10%, at least 50%, at least 80-90%, at least 95%, at least 98%, orat least 99% when the double stranded nucleic acid is introduced into amammalian cell.

In one embodiment, the first and second strands are joined by a chemicallinker.

In another embodiment, the 3′ terminus of the first strand and the 5′terminus of the second strand are joined by a chemical linker.

In an additional embodiment, a nucleotide of the second or first strandis substituted with a modified nucleotide that directs the orientationof Dicer cleavage.

In one embodiment, the nucleic acid, dsNA or hybridization complexpossesses a deoxyribonucleotide, a dideoxyribonucleotide, anacyclonucleotide, a 3′-deoxyadenosine (cordycepin), a3′-azido-3′-deoxythymidine (AZT), a 2′,3′-dideoxyinosine (dd), a2′,3′-dideoxy-3′-thiacytidine (3TC), a2′,3′-didehydro-2′,3′-dideoxythymidine (d4T), a monophosphate nucleotideof 3′-azido-3′-deoxythymidine (AZT), a 2′,3′-dideoxy-3′-thiacytidine(3TC) and a monophosphate nucleotide of2′,3′-didehydro-2′,3′-dideoxythymidine (d4T), a 4-thiouracil, a5-bromouracil, a 5-iodouracil, a 5-(3-aminoallyl)-uracil, a 2′-O-alkylribonucleotide, a 2′-O-methyl ribonucleotide, a 2′-amino ribonucleotide,a 2′-fluoro ribonucleotide, or a locked nucleic acid modifiednucleotide.

In another embodiment, the nucleic acid, dsNA or hybridization complexincludes a phosphonate, a phosphorothioate or a phosphotriesterphosphate backbone modification.

In one embodiment, the nucleic acid, dsNA or hybridization complexincludes a morpholino nucleic acid or a peptide nucleic acid (PNA).

In an additional embodiment, the nucleic acid, dsNA or hybridizationcomplex is attached to a dynamic polyconjugate (DPC).

In one embodiment, the nucleic acid, dsNA or hybridization complex isadministered with a DPC, where the dsNA and DPC are optionally notattached.

In another embodiment, the nucleic acid, dsNA or hybridization complexis attached to a GaNAc moiety, a cholesterol and/or a cholesteroltargeting ligand.

Another aspect of the invention provides a composition of the following:

a dsNA possessing first and second nucleic acid strands, where the firststrand is 15-35 nucleotides in length and the second strand of the dsNAis 19-35 nucleotides in length, where the second oligonucleotide strandis sufficiently complementary to a target transthyretin mRNA sequence ofSEQ ID NOs: 1921-2304 along at least 19 nucleotides of the secondoligonucleotide strand length to reduce transthyretin target mRNAexpression when the double stranded nucleic acid is introduced into amammalian cell;

a dsNA possessing first and second nucleic acid strands, where the firststrand is 15-35 nucleotides in length and the second strand of the dsNAis 19-35 nucleotides in length, where the second oligonucleotide strandis sufficiently complementary to a target transthyretin mRNA sequence ofSEQ ID NOs: 1921-2304 along at least 19 nucleotides of the secondoligonucleotide strand length to reduce transthyretin target mRNAexpression, and where, starting from the 5′ end of the transthyretinmRNA sequence of SEQ ID NOs: 1921-2304 (position 1), mammalian Ago2cleaves the mRNA at a site between positions 9 and 10 of the sequence,when the double stranded nucleic acid is introduced into a mammaliancell;

a dsNA molecule, consisting of: (a) a sense region and an antisenseregion, where the sense region and the antisense region together form aduplex region consisting of 25-35 base pairs and the antisense regionincludes a sequence that is the complement of a sequence of SEQ ID NOs:1921-2304; and (b) from zero to two 3′ overhang regions, where eachoverhang region is six or fewer nucleotides in length, and where,starting from the 5′ end of the transthyretin mRNA sequence of SEQ IDNOs: 1921-2304 (position 1), mammalian Ago2 cleaves the mRNA at a sitebetween positions 9 and 10 of the sequence, when the double strandednucleic acid is introduced into a mammalian cell;

a dsNA possessing first and second nucleic acid strands and a duplexregion of at least 25 base pairs, where the first strand is 25-34nucleotides in length and the second strand of the dsNA is 26-35nucleotides in length and includes 1-5 single-stranded nucleotides atits 3′ terminus, where the second oligonucleotide strand is sufficientlycomplementary to a target transthyretin mRNA sequence of SEQ ID NOs:1921-2304 along at least 19 nucleotides of the second oligonucleotidestrand length to reduce transthyretin target gene expression when thedouble stranded nucleic acid is introduced into a mammalian cell;

a dsNA possessing first and second nucleic acid strands and a duplexregion of at least 25 base pairs, where the first strand is 25-34nucleotides in length and the second strand of the dsNA is 26-35nucleotides in length and includes 1-5 single-stranded nucleotides atits 3′ terminus, where the 3′ terminus of the first oligonucleotidestrand and the 5′ terminus of the second oligonucleotide strand form ablunt end, and the second oligonucleotide strand is sufficientlycomplementary to a target transthyretin sequence of SEQ ID NOs:1921-2304 along at least 19 nucleotides of the second oligonucleotidestrand length to reduce transthyretin mRNA expression when the doublestranded nucleic acid is introduced into a mammalian cell;

a nucleic acid possessing an oligonucleotide strand of 19-35 nucleotidesin length, where the oligonucleotide strand is sufficientlycomplementary to a target transthyretin mRNA sequence of SEQ ID NOs:1921-2304 along at least 19 nucleotides of the oligonucleotide strandlength to reduce transthyretin target mRNA expression when the nucleicacid is introduced into a mammalian cell;

a nucleic acid possessing an oligonucleotide strand of 15-35 nucleotidesin length, where the oligonucleotide strand is hybridizable to a targettransthyretin mRNA sequence of SEQ ID NOs: 1921-2304 along at least 15nucleotides of the oligonucleotide strand length;

a dsNA possessing first and second nucleic acid strands possessing RNA,where the first strand is 15-35 nucleotides in length and the secondstrand of the dsNA is 19-35 nucleotides in length, where the secondoligonucleotide strand is hybridizable to a target transthyretin mRNAsequence of SEQ ID NOs: 1921-2304 along at least 15 nucleotides of thesecond oligonucleotide strand length;

a dsNA possessing first and second nucleic acid strands possessing RNA,where the first strand is 15-35 nucleotides in length and the secondstrand of the dsNA is at least 35 nucleotides in length and optionallyincludes a sequence of at least 25 nucleotides in length of SEQ ID NOs:385-768, where the second oligonucleotide strand is sufficientlycomplementary to a target transthyretin mRNA sequence of SEQ ID NOs:1921-2304 along at least 15 nucleotides of the second oligonucleotidestrand length to reduce transthyretin target mRNA expression when thedouble stranded nucleic acid is introduced into a mammalian cell;

a dsNA possessing a first oligonucleotide strand having a 5′ terminusand a 3′ terminus and a second oligonucleotide strand having a 5′terminus and a 3′ terminus, where the first strand is 25 to 53nucleotide residues in length, where starting from the first nucleotide(position 1) at the 5′ terminus of the first strand, positions 1 to 23of the first strand are ribonucleotides or modified ribonucleotides; thesecond strand is 27 to 53 nucleotide residues in length and includes 23consecutive ribonucleotides or modified ribonucleotides that base pairwith the ribonucleotides or ribonucleotides of positions 1 to 23 of thefirst strand to form a duplex; the 5′ terminus of the first strand andthe 3′ terminus of the second strand form a structure of a blunt end, a1-6 nucleotide 5′ overhang and a 1-6 nucleotide 3′ overhang; the 3′terminus of the first strand and the 5′ terminus of the second strandform a structure of a blunt end, a 1-6 nucleotide 5′ overhang and a 1-6nucleotide 3′ overhang; at least one of positions 24 to the 3′ terminalnucleotide residue of the first strand is a deoxyribonucleotide ormodified ribonucleotide that optionally base pairs with adeoxyribonucleotide of the second strand; and the second strand issufficiently complementary to a target transthyretin mRNA sequence ofSEQ ID NOs: 1921-2304 along at least 15 nucleotides of the secondoligonucleotide strand length to reduce transthyretin target mRNAexpression when the double stranded nucleic acid is introduced into amammalian cell;

a dsNA possessing a first oligonucleotide strand having a 5′ terminusand a 3′ terminus and a second oligonucleotide strand having a 5′terminus and a 3′ terminus, where the second strand is 27 to 53nucleotide residues in length, where starting from the first nucleotide(position 1) at the 5′ terminus of the second strand, positions 1 to 23of the second strand are ribonucleotides or modified ribonucleotides;the first strand is 25 to 53 nucleotide residues in length and includes23 consecutive ribonucleotides or modified ribonucleotides that basepair sufficiently with the ribonucleotides of positions 1 to 23 of thesecond strand to form a duplex; at least one of positions 24 to the 3′terminal nucleotide residue of the second strand is adeoxyribonucleotide or modified ribonucleotide, optionally that basepairs with a deoxyribonucleotide or modified ribonucleotide of the firststrand; and the second strand is sufficiently complementary to a targettransthyretin mRNA sequence of SEQ ID NOs: 1921-2304 along at least 15nucleotides of the second oligonucleotide strand length to reducetransthyretin target mRNA expression when the double stranded nucleicacid is introduced into a mammalian cell;

a dsNA possessing a first oligonucleotide strand having a 5′ terminusand a 3′ terminus and a second oligonucleotide strand having a 5′terminus and a 3′ terminus, where each of the 5′ termini has a 5′terminal nucleotide and each of the 3′ termini has a 3′ terminalnucleotide, where the first strand (or the second strand) is 25-30nucleotide residues in length, where starting from the 5′ terminalnucleotide (position 1) positions 1 to 23 of the first strand (or thesecond strand) include at least 8 ribonucleotides; the second strand (orthe first strand) is 36-66 nucleotide residues in length and, startingfrom the 3′ terminal nucleotide, includes at least 8 ribonucleotides inthe positions paired with positions 1-23 of the first strand to form aduplex; where at least the 3′ terminal nucleotide of the second strand(or the first strand) is unpaired with the first strand (or the secondstrand), and up to 6 consecutive 3′ terminal nucleotides are unpairedwith the first strand (or the second strand), thereby forming a 3′single stranded overhang of 1-6 nucleotides; where the 5′ terminus ofthe second strand (or the first strand) includes from 10-30 consecutivenucleotides which are unpaired with the first strand (or the secondstrand), thereby forming a 10-30 nucleotide single stranded 5′ overhang;where at least the first strand (or the second strand) 5′ terminal and3′ terminal nucleotides are base paired with nucleotides of the secondstrand (or first strand) when the first and second strands are alignedfor maximum complementarity, thereby forming a substantially duplexedregion between the first and second strands; and the second strand issufficiently complementary to a target RNA along at least 19ribonucleotides of the second strand length to reduce target geneexpression when the double stranded nucleic acid is introduced into amammalian cell;

a dsNA possessing a first oligonucleotide strand having a 5′ terminusand a 3′ terminus and a second oligonucleotide strand having a 5′terminus and a 3′ terminus, where each of the 5′ termini has a 5′terminal nucleotide and each of the 3′ termini has a 3′ terminalnucleotide, where the first strand is 25-35 nucleotide residues inlength, where starting from the 5′ terminal nucleotide (position 1)positions 1 to 25 of the second strand include at least 8ribonucleotides; the second strand is 30-66 nucleotide residues inlength and, starting from the 3′ terminal nucleotide, includes at least8 ribonucleotides in the positions paired with positions 1-25 of thefirst strand to form a duplex; where the 5′ terminus of the secondstrand includes from 5-35 consecutive nucleotides which are unpairedwith the first strand, thereby forming a 5-35 nucleotide single stranded5′ overhang; where at least the first strand 5′ terminal and 3′ terminalnucleotides are base paired with nucleotides of the second strand whenthe first and second strands are aligned for maximum complementarity,thereby forming a substantially duplexed region between the first andsecond strands; and the second strand is sufficiently complementary to atarget transthyretin mRNA sequence of SEQ ID NOs: 1921-2304 along atleast 15 nucleotides of the second oligonucleotide strand length toreduce transthyretin target mRNA expression when the double strandednucleic acid is introduced into a mammalian cell;

a dsNA possessing a first oligonucleotide strand having a 5′ terminusand a 3′ terminus and a second oligonucleotide strand having a 5′terminus and a 3′ terminus, where each of the 5′ termini has a 5′terminal nucleotide and each of the 3′ termini has a 3′ terminalnucleotide, where the second strand is 19-30 nucleotide residues inlength and optionally 25-30 nucleotide residues in length, wherestarting from the 5′ terminal nucleotide (position 1) positions 1 to 17(optionally positions 1 to 23) of the second strand include at least 8ribonucleotides; the first strand is 24-66 nucleotide residues in length(optionally 30-66 nucleotide residues in length) and, starting from the3′ terminal nucleotide, includes at least 8 ribonucleotides in thepositions paired with positions 1 to 17 (optionally positions 1 to 23)of the second strand to form a duplex; where the 3′ terminus of thefirst strand and the 5′ terminus of the second strand comprise astructure of a blunt end, a 3′ overhang and a 5′ overhang, optionallywhere the overhang is 1-6 nucleotides in length; where the 5′ terminusof the first strand includes from 5-35 consecutive nucleotides which areunpaired with the second strand, thereby forming a 5-35 nucleotidesingle-stranded 5′ overhang; where at least the second strand 5′terminal and 3′ terminal nucleotides are base paired with nucleotides ofthe first strand when the first and second strands are aligned formaximum complementarity, thereby forming a substantially duplexed regionbetween the first and second strands; and the second strand issufficiently complementary to a target transthyretin mRNA sequence ofSEQ ID NOs: 1921-2304 along at least 15 nucleotides of the secondoligonucleotide strand length to reduce transthyretin target mRNAexpression when the double stranded nucleic acid is introduced into amammalian cell;

a dsNA possessing a first strand and a second strand, where the firststrand and the second strand form a duplex region of 19-25 nucleotidesin length, where the first strand includes a 3′ region that extendsbeyond the first strand-second strand duplex region and includes atetraloop, and the dsNA further includes a discontinuity between the 3′terminus of the first strand and the 5′ terminus of the second strand,and the first or second strand is sufficiently complementary to a targettransthyretin mRNA sequence of SEQ ID NOs: 1921-2304 along at least 15nucleotides of the first or second strand length to reduce transthyretintarget mRNA expression when the dsNA is introduced into a mammaliancell;

a dsNA possessing a first oligonucleotide strand having a 5′ terminusand a 3′ terminus and a second oligonucleotide strand having a 5′terminus and a 3′ terminus, where each of the 5′ termini has a 5′terminal nucleotide and each of the 3′ termini has a 3′ terminalnucleotide, where the first oligonucleotide strand is 25-53 nucleotidesin length and the second is oligonucleotide strand is 25-53 nucleotidesin length, and where the dsNA is sufficiently highly modified tosubstantially prevent dicer cleavage of the dsNA, optionally where thedsNA is cleaved by non-dicer nucleases to yield one or more 19-23nucleotide strand length dsNAs capable of reducing LDH mRNA expressionin a mammalian cell;

an in vivo hybridization complex within a cell of an exogenous nucleicacid sequence and a target Transthyretin mRNA sequence of SEQ ID NOs:1921-2304; and an in vitro hybridization complex within a cell of anexogenous nucleic acid sequence and a target Transthyretin mRNA sequenceof SEQ ID NOs: 1921-2304.

In one embodiment, a dsNA of the invention possesses a duplex region ofat least 25 base pairs, where the dsNA possesses greater potency than a21 mer siRNA directed to the identical at least 19 nucleotides of thetarget transthyretin mRNA in reducing target transthyretin mRNAexpression when assayed in vitro in a mammalian cell at an effectiveconcentration in the environment of a cell of 1 nanomolar or less.

In another embodiment, the dsNA of the invention has a duplex region ofat least 25 base pairs, where the dsNA possesses greater potency than a21 mer siRNA directed to the identical at least 19 nucleotides of thetarget transthyretin mRNA in reducing target transthyretin mRNAexpression when assayed in vitro in a mammalian cell at a concentrationof 1 nanomolar, 200 picomolar, 100 picomolar, 50 picomolar, 20picomolar, 10 picomolar, 5 picomolar, 2, picomolar and 1 picomolar.

In an additional embodiment, the dsNA of the invention possesses four orfewer mismatched nucleic acid residues with respect to the targettransthyretin mRNA sequence along 15 or 19 consecutive nucleotides ofthe at least 15 or 19 nucleotides of the second oligonucleotide strandwhen the 15 or 19 consecutive nucleotides of the second oligonucleotideare aligned for maximum complementarity with the target transthyretinmRNA sequence.

In another embodiment, the dsNA of the invention possesses three orfewer mismatched nucleic acid residues with respect to the targettransthyretin mRNA sequence along 15 or 19 consecutive nucleotides ofthe at least 15 or 19 nucleotides of the second oligonucleotide strandwhen the 15 or 19 consecutive nucleotides of the second oligonucleotideare aligned for maximum complementarity with the target transthyretinmRNA sequence.

Optionally, the dsNA of the invention possesses two or fewer mismatchednucleic acid residues with respect to the target transthyretin mRNAsequence along 15 or 19 consecutive nucleotides of the at least 15 or 19nucleotides of the second oligonucleotide strand when the 15 or 19consecutive nucleotides of the second oligonucleotide are aligned formaximum complementarity with the target transthyretin mRNA sequence.

In certain embodiments, the dsNA of the invention possesses onemismatched nucleic acid residue with respect to the target transthyretinmRNA sequence along 15 or 19 consecutive nucleotides of the at least 15or 19 nucleotides of the second oligonucleotide strand when the 15 or 19consecutive nucleotides of the second oligonucleotide are aligned formaximum complementarity with the target transthyretin mRNA sequence.

In one embodiment, 15 or 19 consecutive nucleotides of the at least 15or 19 nucleotides of the second oligonucleotide strand are completelycomplementary to the target transthyretin mRNA sequence when the 15 or19 consecutive nucleotides of the second oligonucleotide are aligned formaximum complementarity with the target transthyretin mRNA sequence.

Another aspect of the invention provides a method for reducingexpression of a target transthyretin gene in a mammalian cell involvingcontacting a mammalian cell in vitro with a nucleic acid, dsNA orhybridization complex of the invention in an amount sufficient to reduceexpression of a target transthyretin mRNA in the cell.

Optionally, target transthyretin mRNA expression is reduced by an amount(expressed by %) of at least 10%, at least 50% and at least 80-90%.

In one embodiment, transthyretin mRNA levels are reduced by an amount(expressed by %) of at least 90% at least 8 days after the cell iscontacted with the dsNA.

In another embodiment, transthyretin mRNA levels are reduced by anamount (expressed by %) of at least 70% at least 10 days after the cellis contacted with the dsNA.

A further aspect of the invention provides a method for reducingexpression of a target transthyretin mRNA in a mammal possessingadministering a nucleic acid, dsNA or hybridization complex of theinvention to a mammal in an amount sufficient to reduce expression of atarget transthyretin mRNA in the mammal.

In one embodiment, the nucleic acid, dsNA or hybridization complex isformulated in a lipid nanoparticle (LNP).

In another embodiment, the nucleic acid, dsNA or hybridization complexis administered at a dosage of 1 microgram to 5 milligrams per kilogramof the mammal per day, 100 micrograms to 0.5 milligrams per kilogram,0.001 to 0.25 milligrams per kilogram, 0.01 to 20 micrograms perkilogram, 0.01 to 10 micrograms per kilogram, 0.10 to 5 micrograms perkilogram, and 0.1 to 2.5 micrograms per kilogram.

In certain embodiments, the nucleic acid, dsNA or hybridization complexpossesses greater potency than 21 mer siRNAs directed to the identicalat least 19 nucleotides of the target transthyretin mRNA in reducingtarget transthyretin mRNA expression when assayed in vitro in amammalian cell at an effective concentration in the environment of acell of 1 nanomolar or less.

In one embodiment, transthyretin mRNA levels are reduced in a tissue ofthe mammal by an amount (expressed by %) of at least 70% at least 3 daysafter the dsNA is administered to the mammal.

Optionally, the tissue is liver tissue.

In certain embodiments, the administering step involves intravenousinjection, intramuscular injection, intraperitoneal injection, infusion,subcutaneous injection, transdermal, aerosol, rectal, vaginal, topical,oral or inhaled delivery.

Another aspect of the invention provides a method for treating orpreventing a disease or disorder in a subject that involvesadministering to the subject an amount of a nucleic acid, dsNA orhybridization complex of the invention in an amount sufficient to treator prevent the disease or disorder in the subject.

In one embodiment, the disease or disorder is amyloidosis.

Optionally, the subject is human.

A further aspect of the invention provides a formulation that includesthe nucleic acid, dsNA or hybridization complex of the invention, wherethe nucleic acid, dsNA or hybridization complex is present in an amounteffective to reduce target transthyretin mRNA levels when the nucleicacid, dsNA or hybridization complex is introduced into a mammalian cellin vitro by an amount (expressed by %) of at least 10%, at least 50% andat least 80-90%.

In one embodiment, the effective amount is of 1 nanomolar or less, 200picomolar or less, 100 picomolar or less, 50 picomolar or less, 20picomolar or less, 10 picomolar or less, 5 picomolar or less, 2,picomolar or less and 1 picomolar or less in the environment of thecell.

In another embodiment, the nucleic acid, dsNA or hybridization complexis present in an amount effective to reduce target transthyretin mRNAlevels when the nucleic acid, dsNA or hybridization complex isintroduced into a cell of a mammalian subject by an amount (expressed by%) of at least 10%, at least 50% and at least 80-90%.

Optionally, the effective amount is a dosage of 1 microgram to 5milligrams per kilogram of the subject per day, 100 micrograms to 0.5milligrams per kilogram, 0.001 to 0.25 milligrams per kilogram, 0.01 to20 micrograms per kilogram, 0.01 to 10 micrograms per kilogram, 0.10 to5 micrograms per kilogram, or 0.1 to 2.5 micrograms per kilogram.

In another embodiment, the nucleic acid, dsNA or hybridization complexpossesses greater potency than an 21 mer siRNA directed to the identicalat least 19 nucleotides of the target transthyretin mRNA in reducingtarget transthyretin mRNA levels when assayed in vitro in a mammaliancell at an effective concentration in the environment of a cell of 1nanomolar or less.

A further aspect of the invention provides a mammalian cell containingthe nucleic acid, dsNA or hybridization complex of the invention.

Another aspect of the invention provides a pharmaceutical compositionthat includes the nucleic acid, dsNA or hybridization complex of theinvention and a pharmaceutically acceptable carrier.

An additional aspect of the invention provides a kit including thenucleic acid, dsNA or hybridization complex of the invention andinstructions for its use.

A further aspect of the invention provides a composition possessingtransthyretin inhibitory activity consisting essentially of a nucleicacid, dsNA or hybridization complex of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the structures of exemplary DsiRNA agents of the inventiontargeting a site in the transthyretin RNA referred to herein as the“Transthyretin-242” target site. UPPER case=unmodified RNA, lowercase=DNA, Bold=mismatch base pair nucleotides; arrowheads indicateprojected Dicer enzyme cleavage sites; dashed line indicates sensestrand (top strand) sequences corresponding to the projected Argonaute 2(Ago2) cleavage site within the targeted transthyretin sequence.

FIGS. 2A to 2D present primary screen data showing DsiRNA-mediatedknockdown of human transthyretin (FIGS. 2A and 2B) and mousetransthyretin (FIGS. 2C and 2D) in human (Huh7) and mouse (AML12) cells,respectively. For each DsiRNA tested, two independent qPCR ampliconswere assayed (in human cells, amplicons “67-196” and “570-703” wereassayed, while in mouse cells, amplicons “340-469” and “961-1073” wereassayed).

FIGS. 3A to 3H show histograms of human and mouse transthyretininhibitory efficacies observed for indicated DsiRNAs. “P1” indicatesphase 1 (primary screen), while “P2” indicates phase 2. In phase 1,DsiRNAs were tested at 1 nM in the environment of Huh7 cells (human cellassays; FIGS. 3A to 3D) or mouse cells (AML12 cell assays; FIGS. 3E to3H). In phase 2, DsiRNAs were tested at 1 nM, 0.1 nM and 0.03 nM in theenvironment of Huh7 cells. Individual bars represent average human(FIGS. 3A to 3D) or mouse (FIGS. 3E to 3H) transthyretin levels observedin triplicate, with standard errors shown. Human transthyretin levelswere normalized to HPRT and SFRS9 levels, while mouse transthyretinlevels were normalized to HPRT and Rp123 levels.

FIGS. 4A to 4D present histograms showing efficacy data for 24independent TTR-targeting DsiRNA sequences across four different guide(antisense) strand 2′-O-methyl modification patterns (“M17”, “M35”,“M48” and “M8”, respectively, as shown in FIGS. 4A to 4D, noting thatmodification patterns are recited as passenger strand modificationpattern (here, “M107”)-guide strand modification pattern, e.g.,“M107-M17”, “M107-M35”, “M107-M48” or “M107-M8”) in human Huh7 cells at1 nM (both Phase 1 and Phase 3 results are shown), 0.1 nM and 0.03 nM.

FIGS. 5A to 5D present histograms showing efficacy data for nineindependent TTR-targeting DsiRNA sequences across varying passenger(sense) and guide (antisense) strand 2′-O-methyl modification patterns(modification patterns are recited as passenger strand modificationpattern-guide strand modification pattern) in human Huh7 cells at 1 nM(both Phase 2 and Phase 4 results are shown), 0.1 nM and 0.03 nM.

FIGS. 6A to 6D show further modification patterns used in the additionalin vitro TTR inhibition experiments of FIGS. 7A to 7E and 8A to 8F. InFIG. 6D, tetraloop-containing duplex sequences correspond to SEQ ID NO:3479.

FIGS. 7A to 7E show in vitro TTR inhibitory activity results for furthermodified forms of TTR-156, TTR-242, TTR-244 and TTR-255 dsRNAs.

FIGS. 8A to 8F_show in vitro TTR inhibitory activity dose-responsecurves for the further modified forms of TTR-156, TTR-242, TTR-244 andTTR-255 dsRNAs indicated within the figures. In FIGS. 8A and 8B,tetraloop-containing duplex sequences again correspond to SEQ ID NO:3479.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to compositions that contain nucleicacids, for example double stranded RNA (“dsRNA”), and methods forpreparing them, that are capable of reducing the level and/or expressionof the transthyretin gene in vivo or in vitro. One of the strands of thedsRNA contains a region of nucleotide sequence that has a length thatranges from 19 to 35 nucleotides that can direct the destruction and/ortranslational inhibition of the targeted transthyretin transcript.

Definitions

Unless defined otherwise, all technical and scientific terms used hereinhave the meaning commonly understood by a person skilled in the art towhich this invention belongs. The following references provide one ofskill with a general definition of many of the terms used in thisinvention: Singleton et al., Dictionary of Microbiology and MolecularBiology (2nd ed. 1994); The Cambridge Dictionary of Science andTechnology (Walker ed., 1988); The Glossary of Genetics, 5th Ed., R.Rieger et al. (eds.), Springer Verlag (1991); and Hale & Marham, TheHarper Collins Dictionary of Biology (1991). As used herein, thefollowing terms have the meanings ascribed to them below, unlessspecified otherwise.

The present invention features one or more DsiRNA molecules that canmodulate (e.g., inhibit) transthyretin expression. The DsiRNAs of theinvention optionally can be used in combination with modulators of othergenes and/or gene products associated with the maintenance ordevelopment of diseases or disorders associated with transthyretinmisregulation (e.g., tumor formation and/or growth, etc.). The DsiRNAagents of the invention modulate transthyretin RNAs such as thosecorresponding to the cDNA sequences referred to by GenBank AccessionNos. NM_000371.3 (human transthyretin) and NM_013697.5 (mousetransthyretin), which are referred to herein generally as“transthyretin.”

The below description of the various aspects and embodiments of theinvention is provided with reference to exemplary transthyretin RNAs,generally referred to herein as transthyretin. However, such referenceis meant to be exemplary only and the various aspects and embodiments ofthe invention are also directed to alternate transthyretin RNAs, such asmutant transthyretin RNAs or additional transthyretin splice variants.Certain aspects and embodiments are also directed to other genesinvolved in transthyretin pathways, including genes whose misregulationacts in association with that of transthyretin (or is affected oraffects transthyretin regulation) to produce phenotypic effects that maybe targeted for treatment (e.g., tumor formation and/or growth, etc.).BAK1, Noxa, BCL2L11, Bcl-2-associated death promoter, PCNA, DAD1, TNKSand BH3 interacting domain death agonist are examples of genes thatinteract with transthyretin. Such additional genes, including those ofpathways that act in coordination with transthyretin, can be targetedusing dsRNA and the methods described herein for use oftransthyretin-targeting dsRNAs. Thus, the inhibition and the effects ofsuch inhibition of the other genes can be performed as described herein.

The term “transthyretin” refers to nucleic acid sequences encoding atransthyretin protein, peptide, or polypeptide (e.g., transthyretintranscripts, such as the sequences of transthyretin Genbank AccessionNos. NM_000371.3 and NM_013697.5). In certain embodiments, the term“transthyretin” is also meant to include other transthyretin encodingsequence, such as other transthyretin isoforms, mutant transthyretingenes, splice variants of transthyretin genes, and transthyretin genepolymorphisms. The term “transthyretin” is also used to refer to thepolypeptide gene product of an transthyretin gene/transript, e.g., antransthyretin protein, peptide, or polypeptide, such as those encoded bytransthyretin Genbank Accession Nos. NP_000362.1 and NP_038725.1.

As used herein, a “transthyretin-associated disease or disorder” refersto a disease or disorder known in the art to be associated with alteredtransthyretin expression, level and/or activity. Notably, a“transthyretin-associated disease or disorder” includes diseases ordisorders of the liver and other organs including, but not limited to,TTR amyloidosis, e.g., familial amyloidotic polyneuropathy (FAP),familial amyloidotic cardiomyopathy (FAC) and leptomeningeal/CNS(Central Nervous System) amyloidosis.

In certain embodiments, dsRNA-mediated inhibition of a transthyretintarget sequence is assessed. In such embodiments, transthyretin RNAlevels can be assessed by art-recognized methods (e.g., RT-PCR, Northernblot, expression array, etc.), optionally via comparison oftransthyretin levels in the presence of an anti-transthyretin dsRNA ofthe invention relative to the absence of such an anti-transthyretindsRNA. In certain embodiments, transthyretin levels in the presence ofan anti-transthyretin dsRNA are compared to those observed in thepresence of vehicle alone, in the presence of a dsRNA directed againstan unrelated target RNA, or in the absence of any treatment.

It is also recognized that levels of transthyretin protein can beassessed and that transthyretin protein levels are, under differentconditions, either directly or indirectly related to transthyretin RNAlevels and/or the extent to which a dsRNA inhibits transthyretinexpression, thus art-recognized methods of assessing transthyretinprotein levels (e.g., Western blot, immunoprecipitation, otherantibody-based methods, etc.) can also be employed to examine theinhibitory effect of a dsRNA of the invention.

An anti-transthyretin dsRNA of the invention is deemed to possess“transthyretin inhibitory activity” if a statistically significantreduction in transthyretin RNA (or when the transthyretin protein isassessed, transthyretin protein levels) is seen when ananti-transthyretin dsRNA of the invention is administered to a system(e.g., cell-free in vitro system), cell, tissue or organism, as comparedto a selected control. The distribution of experimental values and thenumber of replicate assays performed will tend to dictate the parametersof what levels of reduction in transthyretin RNA (either as a % or inabsolute terms) is deemed statistically significant (as assessed bystandard methods of determining statistical significance known in theart). However, in certain embodiments, “transthyretin inhibitoryactivity” is defined based upon a % or absolute level of reduction inthe level of transthyretin in a system, cell, tissue or organism. Forexample, in certain embodiments, a dsRNA of the invention is deemed topossess transthyretin inhibitory activity if at least a 5% reduction orat least a 10% reduction in transthyretin RNA is observed in thepresence of a dsRNA of the invention relative to transthyretin levelsseen for a suitable control. (For example, in vivo transthyretin levelsin a tissue and/or subject can, in certain embodiments, be deemed to beinhibited by a dsRNA agent of the invention if, e.g., a 5% or 10%reduction in transthyretin levels is observed relative to a control.) Incertain other embodiments, a dsRNA of the invention is deemed to possesstransthyretin inhibitory activity if transthyretin RNA levels areobserved to be reduced by at least 15% relative to a selected control,by at least 20% relative to a selected control, by at least 25% relativeto a selected control, by at least 30% relative to a selected control,by at least 35% relative to a selected control, by at least 40% relativeto a selected control, by at least 45% relative to a selected control,by at least 50% relative to a selected control, by at least 55% relativeto a selected control, by at least 60% relative to a selected control,by at least 65% relative to a selected control, by at least 70% relativeto a selected control, by at least 75% relative to a selected control,by at least 80% relative to a selected control, by at least 85% relativeto a selected control, by at least 90% relative to a selected control,by at least 95% relative to a selected control, by at least 96% relativeto a selected control, by at least 97% relative to a selected control,by at least 98% relative to a selected control or by at least 99%relative to a selected control. In some embodiments, complete inhibitionof transthyretin is required for a dsRNA to be deemed to possesstransthyretin inhibitory activity. In certain models (e.g., cellculture), a dsRNA is deemed to possess transthyretin inhibitory activityif at least a 50% reduction in transthyretin levels is observed relativeto a suitable control. In certain other embodiments, a dsRNA is deemedto possess transthyretin inhibitory activity if at least an 80%reduction in transthyretin levels is observed relative to a suitablecontrol.

By way of specific example, in Example 2 below, a series of DsiRNAstargeting transthyretin were tested for the ability to reducetransthyretin mRNA levels in human Huh7 or mouse AML12 cells in vitro,at 1 nM concentrations in the environment of such cells and in thepresence of a transfection agent (Lipofectamine™ RNAiMAX, Invitrogen).Within Example 2 below, transthyretin inhibitory activity was ascribedto those DsiRNAs that were observed to effect at least a 50% reductionof transthyretin mRNA levels under the assayed conditions. It iscontemplated that transthyretin inhibitory activity could also beattributed to a dsRNA under either more or less stringent conditionsthan those employed for Example 2 below, even when the same or a similarassay and conditions are employed. For example, in certain embodiments,a tested dsRNA of the invention is deemed to possess transthyretininhibitory activity if at least a 10% reduction, at least a 20%reduction, at least a 30% reduction, at least a 40% reduction, at leasta 50% reduction, at least a 60% reduction, at least a 70% reduction, atleast a 75% reduction, at least an 80% reduction, at least an 85%reduction, at least a 90% reduction, or at least a 95% reduction intransthyretin mRNA levels is observed in a mammalian cell line in vitroat 1 nM dsRNA concentration or lower in the environment of a cell,relative to a suitable control.

Use of other endpoints for determination of whether a double strandedRNA of the invention possesses transthyretin inhibitory activity is alsocontemplated. Specifically, in one embodiment, in addition to or as analternative to assessing transthyretin mRNA levels, the ability of atested dsRNA to reduce transthyretin protein levels (e.g., at 48 hoursafter contacting a mammalian cell in vitro or in vivo) is assessed, anda tested dsRNA is deemed to possess transthyretin inhibitory activity ifat least a 10% reduction, at least a 20% reduction, at least a 30%reduction, at least a 40% reduction, at least a 50% reduction, at leasta 60% reduction, at least a 70% reduction, at least a 75% reduction, atleast an 80% reduction, at least an 85% reduction, at least a 90%reduction, or at least a 95% reduction in transthyretin protein levelsis observed in a mammalian cell contacted with the assayed doublestranded RNA in vitro or in vivo, relative to a suitable control.Additional endpoints contemplated include, e.g., assessment of aphenotype associated with reduction of transthyretin levels—e.g.,reduction of phenotypes associated with elevated levels of TTR depositsthroughout the body.

Transthyretin inhibitory activity can also be evaluated over time(duration) and over concentration ranges (potency), with assessment ofwhat constitutes a dsRNA possessing transthyretin inhibitory activityadjusted in accordance with concentrations administered and duration oftime following administration. Thus, in certain embodiments, a dsRNA ofthe invention is deemed to possess transthyretin inhibitory activity ifat least a 50% reduction in transthyretin activity is observed/persistsat a duration of time of 2 hours, 5 hours, 10 hours, 1 day, 2 days, 3days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days or moreafter administration of the dsRNA to a cell or organism. In additionalembodiments, a dsRNA of the invention is deemed to be a potenttransthyretin inhibitory agent if transthyretin inhibitory activity(e.g., in certain embodiments, at least 50% inhibition of transthyretin)is observed at a concentration of 1 nM or less, 500 pM or less, 200 pMor less, 100 pM or less, 50 pM or less, 20 pM or less, 10 pM or less, 5pM or less, 2 pM or less or even 1 pM or less in the environment of acell, for example, within an in vitro assay for transthyretin inhibitoryactivity as described herein. In certain embodiments, a potenttransthyretin inhibitory dsRNA of the invention is defined as one thatis capable of transthyretin inhibitory activity (e.g., in certainembodiments, at least 20% reduction of transthyretin levels) at aformulated concentration of 10 mg/kg or less when administered to asubject in an effective delivery vehicle (e.g., an effective lipidnanoparticle formulation). Preferably, a potent transthyretin inhibitorydsRNA of the invention is defined as one that is capable oftransthyretin inhibitory activity (e.g., in certain embodiments, atleast 50% reduction of transthyretin levels) at a formulatedconcentration of 5 mg/kg or less when administered to a subject in aneffective delivery vehicle. More preferably, a potent transthyretininhibitory dsRNA of the invention is defined as one that is capable oftransthyretin inhibitory activity (e.g., in certain embodiments, atleast 50% reduction of transthyretin levels) at a formulatedconcentration of 5 mg/kg or less when administered to a subject in aneffective delivery vehicle. Optionally, a potent transthyretininhibitory dsRNA of the invention is defined as one that is capable oftransthyretin inhibitory activity (e.g., in certain embodiments, atleast 50% reduction of transthyretin levels) at a formulatedconcentration of 2 mg/kg or less, or even 1 mg/kg or less, whenadministered to a subject in an effective delivery vehicle.

In certain embodiments, potency of a dsRNA of the invention isdetermined in reference to the number of copies of a dsRNA present inthe cytoplasm of a target cell that are required to achieve a certainlevel of target gene knockdown. For example, in certain embodiments, apotent dsRNA is one capable of causing 50% or greater knockdown of atarget mRNA when present in the cytoplasm of a target cell at a copynumber of 1000 or fewer RISC-loaded antisense strands per cell. Morepreferably, a potent dsRNA is one capable of producing 50% or greaterknockdown of a target mRNA when present in the cytoplasm of a targetcell at a copy number of 500 or fewer RISC-loaded antisense strands percell. Optionally, a potent dsRNA is one capable of producing 50% orgreater knockdown of a target mRNA when present in the cytoplasm of atarget cell at a copy number of 300 or fewer RISC-loaded antisensestrands per cell.

In further embodiments, the potency of a DsiRNA of the invention can bedefined in reference to a 19 to 23 mer dsRNA directed to the same targetsequence within the same target gene. For example, a DsiRNA of theinvention that possesses enhanced potency relative to a corresponding 19to 23 mer dsRNA can be a DsiRNA that reduces a target gene by anadditional 5% or more, an additional 10% or more, an additional 20% ormore, an additional 30% or more, an additional 40% or more, or anadditional 50% or more as compared to a corresponding 19 to 23 merdsRNA, when assayed in an in vitro assay as described herein at asufficiently low concentration to allow for detection of a potencydifference (e.g., transfection concentrations at or below 1 nM in theenvironment of a cell, at or below 100 pM in the environment of a cell,at or below 10 pM in the environment of a cell, at or below 1 nM in theenvironment of a cell, in an in vitro assay as described herein;notably, it is recognized that potency differences can be best detectedvia performance of such assays across a range of concentrations—e.g.,0.1 pM to 10 nM—for purpose of generating a dose-response curve andidentifying an IC₅₀ value associated with a DsiRNA/dsRNA).

Transthyretin inhibitory levels and/or transthyretin levels may also beassessed indirectly, e.g., measurement of a reduction of amyloidosisphenotype(s) in a subject may be used to assess transthyretin levelsand/or transthyretin inhibitory efficacy of a double-stranded nucleicacid of the instant invention.

In certain embodiments, the phrase “consists essentially of” is used inreference to the anti-transthyretin dsRNAs of the invention. In somesuch embodiments, “consists essentially of” refers to a composition thatcomprises a dsRNA of the invention which possesses at least a certainlevel of transthyretin inhibitory activity (e.g., at least 50%transthyretin inhibitory activity) and that also comprises one or moreadditional components and/or modifications that do not significantlyimpact the transthyretin inhibitory activity of the dsRNA. For example,in certain embodiments, a composition “consists essentially of” a dsRNAof the invention where modifications of the dsRNA of the inventionand/or dsRNA-associated components of the composition do not alter thetransthyretin inhibitory activity (optionally including potency orduration of transthyretin inhibitory activity) by greater than 3%,greater than 5%, greater than 10%, greater than 15%, greater than 20%,greater than 25%, greater than 30%, greater than 35%, greater than 40%,greater than 45%, or greater than 50% relative to the dsRNA of theinvention in isolation. In certain embodiments, a composition is deemedto consist essentially of a dsRNA of the invention even if more dramaticreduction of transthyretin inhibitory activity (e.g., 80% reduction, 90%reduction, etc. in efficacy, duration and/or potency) occurs in thepresence of additional components or modifications, yet wheretransthyretin inhibitory activity is not significantly elevated (e.g.,observed levels of transthyretin inhibitory activity are within 10%those observed for the isolated dsRNA of the invention) in the presenceof additional components and/or modifications.

As used herein, the term “nucleic acid” refers to deoxyribonucleotides,ribonucleotides, or modified nucleotides, and polymers thereof insingle- or double-stranded form. The term encompasses nucleic acidscontaining known nucleotide analogs or modified backbone residues orlinkages, which are synthetic, naturally occurring, and non-naturallyoccurring, which have similar binding properties as the referencenucleic acid, and which are metabolized in a manner similar to thereference nucleotides. Examples of such analogs include, withoutlimitation, phosphorothioates, phosphoramidates, methyl phosphonates,chiral-methyl phosphonates, 2-O-methyl ribonucleotides, peptide-nucleicacids (PNAs) and unlocked nucleic acids (UNAs; see, e.g., Jensen et al.Nucleic Acids Symposium Series 52: 133-4), and derivatives thereof.

As used herein, “nucleotide” is used as recognized in the art to includethose with natural bases (standard), and modified bases well known inthe art. Such bases are generally located at the 1′ position of anucleotide sugar moiety. Nucleotides generally comprise a base, sugarand a phosphate group. The nucleotides can be unmodified or modified atthe sugar, phosphate and/or base moiety, (also referred tointerchangeably as nucleotide analogs, modified nucleotides, non-naturalnucleotides, non-standard nucleotides and other; see, e.g., Usman andMcSwiggen, supra; Eckstein, et al., International PCT Publication No. WO92/07065; Usman et al, International PCT Publication No. WO 93/15187;Uhlman & Peyman, supra, all are hereby incorporated by referenceherein). There are several examples of modified nucleic acid bases knownin the art as summarized by Limbach, et al, Nucleic Acids Res. 22:2183,1994. Some of the non-limiting examples of base modifications that canbe introduced into nucleic acid molecules include, hypoxanthine, purine,pyridin-4-one, pyridin-2-one, phenyl, pseudouracil, 2,4,6-trimethoxybenzene, 3-methyl uracil, dihydrouridine, naphthyl, aminophenyl,5-alkylcytidines (e.g., 5-methylcytidine), 5-alkyluridines (e.g.,ribothymidine), 5-halouridine (e.g., 5-bromouridine) or 6-azapyrimidinesor 6-alkylpyrimidines (e.g. 6-methyluridine), propyne, and others(Burgin, et al., Biochemistry 35:14090, 1996; Uhlman & Peyman, supra).By “modified bases” in this aspect is meant nucleotide bases other thanadenine, guanine, cytosine and uracil at 1′ position or theirequivalents.

As used herein, “modified nucleotide” refers to a nucleotide that hasone or more modifications to the nucleoside, the nucleobase, pentosering, or phosphate group. For example, modified nucleotides excluderibonucleotides containing adenosine monophosphate, guanosinemonophosphate, uridine monophosphate, and cytidine monophosphate anddeoxyribonucleotides containing deoxyadenosine monophosphate,deoxyguanosine monophosphate, deoxythymidine monophosphate, anddeoxycytidine monophosphate. Modifications include those naturallyoccurring that result from modification by enzymes that modifynucleotides, such as methyltransferases. Modified nucleotides alsoinclude synthetic or non-naturally occurring nucleotides. Synthetic ornon-naturally occurring modifications in nucleotides include those with2′ modifications, e.g., 2′-methoxyethoxy, 2′-fluoro, 2′-allyl,2′-O-[2-(methylamino)-2-oxoethyl], 4′-thio, 4′-CH₂—O-2′-bridge,4′-(CH₂)2-0-2′-bridge, 2′-LNA or other bicyclic or “bridged” nucleosideanalog, and 2′-O—(N-methylcarbamate) or those comprising base analogs.In connection with 2-modified nucleotides as described for the presentdisclosure, by “amino” is meant 2′-NH₂ or 2′-O—NH₂, which can bemodified or unmodified. Such modified groups are described, e.g., inEckstein et al., U.S. Pat. No. 5,672,695 and Matulic-Adamic et al., U.S.Pat. No. 6,248,878. “Modified nucleotides” of the instant invention canalso include nucleotide analogs as described above.

In reference to the nucleic acid molecules of the present disclosure,modifications may exist upon these agents in patterns on one or bothstrands of the double stranded ribonucleic acid (dsRNA). As used herein,“alternating positions” refers to a pattern where every other nucleotideis a modified nucleotide or there is an unmodified nucleotide (e.g., anunmodified ribonucleotide) between every modified nucleotide over adefined length of a strand of the dsRNA (e.g., 5′-MNMNMN-3′;3′-MNMNMN-5′; where M is a modified nucleotide and N is an unmodifiednucleotide). The modification pattern starts from the first nucleotideposition at either the 5′ or 3′ terminus according to a positionnumbering convention, e.g., as described herein (in certain embodiments,position 1 is designated in reference to the terminal residue of astrand following a projected Dicer cleavage event of a DsiRNA agent ofthe invention; thus, position 1 does not always constitute a 3′ terminalor 5′ terminal residue of a pre-processed agent of the invention). Thepattern of modified nucleotides at alternating positions may run thefull length of the strand, but in certain embodiments includes at least4, 6, 8, 10, 12, 14 nucleotides containing at least 2, 3, 4, 5, 6 or 7modified nucleotides, respectively. As used herein, “alternating pairsof positions” refers to a pattern where two consecutive modifiednucleotides are separated by two consecutive unmodified nucleotides overa defined length of a strand of the dsRNA (e.g., 5′-MMNNMMNNMMNN-3′;3′-MMNNMMNNMMNN-5′; where M is a modified nucleotide and N is anunmodified nucleotide). The modification pattern starts from the firstnucleotide position at either the 5′ or 3′ terminus according to aposition numbering convention such as those described herein. Thepattern of modified nucleotides at alternating positions may run thefull length of the strand, but preferably includes at least 8, 12, 16,20, 24, 28 nucleotides containing at least 4, 6, 8, 10, 12 or 14modified nucleotides, respectively. It is emphasized that the abovemodification patterns are exemplary and are not intended as limitationson the scope of the invention.

As used herein, “base analog” refers to a heterocyclic moiety which islocated at the 1′ position of a nucleotide sugar moiety in a modifiednucleotide that can be incorporated into a nucleic acid duplex (or theequivalent position in a nucleotide sugar moiety substitution that canbe incorporated into a nucleic acid duplex). In the dsRNAs of theinvention, a base analog is generally either a purine or pyrimidine baseexcluding the common bases guanine (G), cytosine (C), adenine (A),thymine (T), and uracil (U). Base analogs can duplex with other bases orbase analogs in dsRNAs. Base analogs include those useful in thecompounds and methods of the invention, e.g., those disclosed in U.S.Pat. Nos. 5,432,272 and 6,001,983 to Benner and US Patent PublicationNo. 20080213891 to Manoharan, which are herein incorporated byreference. Non-limiting examples of bases include hypoxanthine (I),xanthine (X), 3β-D-ribofuranosyl-(2,6-diaminopyrimidine) (K),3-β-D-ribofuranosyl-(1-methyl-pyrazolo[4,3-d]pyrimidine-5,7(4H,6H)-d-ione)(P), iso-cytosine (iso-C), iso-guanine (iso-G),1-β-D-ribofuranosyl-(5-nitroindole),1-β-D-ribofuranosyl-(3-nitropyrrole), 5-bromouracil, 2-aminopurine,4-thio-dT, 7-(2-thienyl)-imidazo[4,5-b]pyridine (Ds) andpyrrole-2-carbaldehyde (Pa), 2-amino-6-(2-thienyl)purine (S),2-oxopyridine (Y), difluorotolyl, 4-fluoro-6-methylbenzimidazole,4-methylbenzimidazole, 3-methyl isocarbostyrilyl, 5-methylisocarbostyrilyl, and 3-methyl-7-propynyl isocarbostyrilyl,7-azaindolyl, 6-methyl-7-azaindolyl, imidizopyridinyl,9-methyl-imidizopyridinyl, pyrrolopyrizinyl, isocarbostyrilyl,7-propynyl isocarbostyrilyl, propynyl-7-azaindolyl,2,4,5-trimethylphenyl, 4-methylindolyl, 4,6-dimethylindolyl, phenyl,napthalenyl, anthracenyl, phenanthracenyl, pyrenyl, stilbenzyl,tetracenyl, pentacenyl, and structural derivates thereof (Schweitzer etal., J. Org. Chem., 59:7238-7242 (1994); Berger et al., Nucleic AcidsResearch, 28(15):2911-2914 (2000); Moran et al., J. Am. Chem. Soc.,119:2056-2057 (1997); Morales et al., J. Am. Chem. Soc., 121:2323-2324(1999); Guckian et al., J. Am. Chem. Soc., 118:8182-8183 (1996); Moraleset al., J. Am. Chem. Soc., 122(6):1001-1007 (2000); McMinn et al., J.Am. Chem. Soc., 121:11585-11586 (1999); Guckian et al., J. Org. Chem.,63:9652-9656 (1998); Moran et al., Proc. Natl. Acad. Sci.,94:10506-10511 (1997); Das et al., J. Chem. Soc., Perkin Trans.,1:197-206 (2002); Shibata et al., J. Chem. Soc., Perkin Trans., 1:1605-1611 (2001); Wu et al., J. Am. Chem. Soc., 122(32):7621-7632(2000); O'Neill et al., J. Org. Chem., 67:5869-5875 (2002); Chaudhuri etal., J. Am. Chem. Soc., 117:10434-10442 (1995); and U.S. Pat. No.6,218,108). Base analogs may also be a universal base.

As used herein, “universal base” refers to a heterocyclic moiety locatedat the 1′ position of a nucleotide sugar moiety in a modifiednucleotide, or the equivalent position in a nucleotide sugar moietysubstitution, that, when present in a nucleic acid duplex, can bepositioned opposite more than one type of base without altering thedouble helical structure (e.g., the structure of the phosphatebackbone). Additionally, the universal base does not destroy the abilityof the single stranded nucleic acid in which it resides to duplex to atarget nucleic acid. The ability of a single stranded nucleic acidcontaining a universal base to duplex a target nucleic can be assayed bymethods apparent to one in the art (e.g., UV absorbance, circulardichroism, gel shift, single stranded nuclease sensitivity, etc.).

Additionally, conditions under which duplex formation is observed may bevaried to determine duplex stability or formation, e.g., temperature, asmelting temperature (Tm) correlates with the stability of nucleic acidduplexes. Compared to a reference single stranded nucleic acid that isexactly complementary to a target nucleic acid, the single strandednucleic acid containing a universal base forms a duplex with the targetnucleic acid that has a lower Tm than a duplex formed with thecomplementary nucleic acid. However, compared to a reference singlestranded nucleic acid in which the universal base has been replaced witha base to generate a single mismatch, the single stranded nucleic acidcontaining the universal base forms a duplex with the target nucleicacid that has a higher Tm than a duplex formed with the nucleic acidhaving the mismatched base.

Some universal bases are capable of base pairing by forming hydrogenbonds between the universal base and all of the bases guanine (G),cytosine (C), adenine (A), thymine (T), and uracil (U) under base pairforming conditions. A universal base is not a base that forms a basepair with only one single complementary base. In a duplex, a universalbase may form no hydrogen bonds, one hydrogen bond, or more than onehydrogen bond with each of G, C, A, T, and U opposite to it on theopposite strand of a duplex. Preferably, the universal bases does notinteract with the base opposite to it on the opposite strand of aduplex. In a duplex, base pairing between a universal base occurswithout altering the double helical structure of the phosphate backbone.A universal base may also interact with bases in adjacent nucleotides onthe same nucleic acid strand by stacking interactions. Such stackinginteractions stabilize the duplex, especially in situations where theuniversal base does not form any hydrogen bonds with the base positionedopposite to it on the opposite strand of the duplex. Non-limitingexamples of universal-binding nucleotides include inosine,1-β-D-ribofuranosyl-5-nitroindole, and/or1-β-D-ribofuranosyl-3-nitropyrrole (US Pat. Appl. Publ. No. 20070254362to Quay et al.; Van Aerschot et al., An acyclic 5-nitroindazolenucleoside analogue as ambiguous nucleoside. Nucleic Acids Res. 1995Nov. 11; 23(21):4363-70; Loakes et al., 3-Nitropyrrole and 5-nitroindoleas universal bases in primers for DNA sequencing and PCR. Nucleic AcidsRes. 1995 Jul. 11; 23(13):2361-6; Loakes and Brown, 5-Nitroindole as anuniversal base analogue. Nucleic Acids Res. 1994 Oct. 11;22(20):4039-43).

As used herein, “loop” refers to a structure formed by a single strandof a nucleic acid, in which complementary regions that flank aparticular single stranded nucleotide region hybridize in a way that thesingle stranded nucleotide region between the complementary regions isexcluded from duplex formation or Watson-Crick base pairing. A loop is asingle stranded nucleotide region of any length. Examples of loopsinclude the unpaired nucleotides present in such structures as hairpins,stem loops, or extended loops.

As used herein, “extended loop” in the context of a dsRNA refers to asingle stranded loop and in addition 1, 2, 3, 4, 5, 6 or up to 20 basepairs or duplexes flanking the loop. In an extended loop, nucleotidesthat flank the loop on the 5′ side form a duplex with nucleotides thatflank the loop on the 3′ side. An extended loop may form a hairpin orstem loop.

As used herein, “tetraloop” in the context of a dsRNA refers to a loop(a single stranded region) consisting of four nucleotides that forms astable secondary structure that contributes to the stability of adjacentWatson-Crick hybridized nucleotides. Without being limited to theory, atetraloop may stabilize an adjacent Watson-Crick base pair by stackinginteractions. In addition, interactions among the four nucleotides in atetraloop include but are not limited to non-Watson-Crick base pairing,stacking interactions, hydrogen bonding, and contact interactions(Cheong et al., Nature 1990 Aug. 16; 346(6285):680-2; Heus and Pardi,Science 1991 Jul. 12; 253(5016):191-4). A tetraloop confers an increasein the melting temperature (Tm) of an adjacent duplex that is higherthan expected from a simple model loop sequence consisting of fourrandom bases. For example, a tetraloop can confer a melting temperatureof at least 55° C. in 10 mM NaHPO₄ to a hairpin comprising a duplex ofat least 2 base pairs in length. A tetraloop may containribonucleotides, deoxyribonucleotides, modified nucleotides, andcombinations thereof. Examples of RNA tetraloops include the UNCG familyof tetraloops (e.g., UUCG), the GNRA family of tetraloops (e.g., GAAA),and the CUUG tetraloop. (Woese et al., Proc Natl Acad Sci USA. 1990November; 87(21):8467-71; Antao et al., Nucleic Acids Res. 1991 Nov. 11;19(21):5901-5). Examples of DNA tetraloops include the d(GNNA) family oftetraloops (e.g., d(GTTA), the d(GNRA)) family of tetraloops, thed(GNAB) family of tetraloops, the d(CNNG) family of tetraloops, thed(TNCG) family of tetraloops (e.g., d(TTCG)). (Nakano et al.Biochemistry, 41 (48), 14281-14292, 2002; SHINJI et al. Nippon KagakkaiKoen Yokoshu VOL. 78th; NO. 2; PAGE. 731 (2000).) As used herein, theterm “siRNA” refers to a double stranded nucleic acid in which eachstrand comprises RNA, RNA analog(s) or RNA and DNA. The siRNA comprisesbetween 19 and 23 nucleotides or comprises 21 nucleotides. The siRNAtypically has 2 bp overhangs on the 3′ ends of each strand such that theduplex region in the siRNA comprises 17-21 nucleotides, or 19nucleotides. Typically, the antisense strand of the siRNA issufficiently complementary with the target sequence of the transthyretingene/RNA.

In certain embodiments, an anti-transthyretin DsiRNA of the instantinvention possesses strand lengths of at least 25 nucleotides.Accordingly, in certain embodiments, an anti-transthyretin DsiRNAcontains one oligonucleotide sequence, a first sequence, that is atleast 25 nucleotides in length and no longer than 35 or up to 50 or morenucleotides. This sequence of RNA can be between 26 and 35, 26 and 34,26 and 33, 26 and 32, 26 and 31, 26 and 30, and 26 and 29 nucleotides inlength. This sequence can be 27 or 28 nucleotides in length or 27nucleotides in length. The second sequence of the DsiRNA agent can be asequence that anneals to the first sequence under biological conditions,such as within the cytoplasm of a eukaryotic cell. Generally, the secondoligonucleotide sequence will have at least 19 complementary base pairswith the first oligonucleotide sequence, more typically the secondoligonucleotide sequence will have 21 or more complementary base pairs,or 25 or more complementary base pairs with the first oligonucleotidesequence. In one embodiment, the second sequence is the same length asthe first sequence, and the DsiRNA agent is blunt ended. In anotherembodiment, the ends of the DsiRNA agent have one or more overhangs.

In certain embodiments, the first and second oligonucleotide sequencesof the DsiRNA agent exist on separate oligonucleotide strands that canbe and typically are chemically synthesized. In some embodiments, bothstrands are between 26 and 35 nucleotides in length. In otherembodiments, both strands are between 25 and 30 or 26 and 30 nucleotidesin length. In one embodiment, both strands are 27 nucleotides in length,are completely complementary and have blunt ends. In certain embodimentsof the instant invention, the first and second sequences of ananti-transthyretin DsiRNA exist on separate RNA oligonucleotides(strands). In one embodiment, one or both oligonucleotide strands arecapable of serving as a substrate for Dicer. In other embodiments, atleast one modification is present that promotes Dicer to bind to thedouble-stranded RNA structure in an orientation that maximizes thedouble-stranded RNA structure's effectiveness in inhibiting geneexpression. In certain embodiments of the instant invention, theanti-transthyretin DsiRNA agent is comprised of two oligonucleotidestrands of differing lengths, with the anti-transthyretin DsiRNApossessing a blunt end at the 3′ terminus of a first strand (sensestrand) and a 3′ overhang at the 3′ terminus of a second strand(antisense strand). The DsiRNA can also contain one or moredeoxyribonucleic acid (DNA) base substitutions.

Suitable DsiRNA compositions that contain two separate oligonucleotidescan be chemically linked outside their annealing region by chemicallinking groups. Many suitable chemical linking groups are known in theart and can be used. Suitable groups will not block Dicer activity onthe DsiRNA and will not interfere with the directed destruction of theRNA transcribed from the target gene. Alternatively, the two separateoligonucleotides can be linked by a third oligonucleotide such that ahairpin structure is produced upon annealing of the two oligonucleotidesmaking up the DsiRNA composition. The hairpin structure will not blockDicer activity on the DsiRNA and will not interfere with the directeddestruction of the target RNA.

The dsRNA molecule can be designed such that every residue of theantisense strand is complementary to a residue in the target molecule.Alternatively, substitutions can be made within the molecule to increasestability and/or enhance processing activity of said molecule.Substitutions can be made within the strand or can be made to residuesat the ends of the strand. In certain embodiments, substitutions and/ormodifications are made at specific residues within a DsiRNA agent. Suchsubstitutions and/or modifications can include, e.g.,deoxy-modifications at one or more residues of positions 1, 2 and 3 whennumbering from the 3′ terminal position of the sense strand of a DsiRNAagent; and introduction of 2′-O-alkyl (e.g., 2′-O-methyl) modificationsat the 3′ terminal residue of the antisense strand of DsiRNA agents,with such modifications also being performed at overhang positions ofthe 3′ portion of the antisense strand and at alternating residues ofthe antisense strand of the DsiRNA that are included within the regionof a DsiRNA agent that is processed to form an active siRNA agent. Thepreceding modifications are offered as exemplary, and are not intendedto be limiting in any manner. Further consideration of the structure ofpreferred DsiRNA agents, including further description of themodifications and substitutions that can be performed upon theanti-transthyretin DsiRNA agents of the instant invention, can be foundbelow.

Where a first sequence is referred to as “substantially complementary”with respect to a second sequence herein, the two sequences can be fullycomplementary, or they may form one or more, but generally not more than4, 3 or 2 mismatched base pairs upon hybridization, while retaining theability to hybridize under the conditions most relevant to theirultimate application. However, where two oligonucleotides are designedto form, upon hybridization, one or more single stranded overhangs, suchoverhangs shall not be regarded as mismatches with regard to thedetermination of complementarity. For example, a dsRNA comprising oneoligonucleotide 21 nucleotides in length and another oligonucleotide 23nucleotides in length, wherein the longer oligonucleotide comprises asequence of 21 nucleotides that is fully complementary to the shorteroligonucleotide, may yet be referred to as “fully complementary” for thepurposes of the invention.

The term “double-stranded RNA” or “dsRNA”, as used herein, refers to acomplex of ribonucleic acid molecules, having a duplex structurecomprising two anti-parallel and substantially complementary, as definedabove, nucleic acid strands. The two strands forming the duplexstructure may be different portions of one larger RNA molecule, or theymay be separate RNA molecules. Where separate RNA molecules, such dsRNAare often referred to as siRNA (“short interfering RNA”) or DsiRNA(“Dicer substrate siRNAs”). Where the two strands are part of one largermolecule, and therefore are connected by an uninterrupted chain ofnucleotides between the 3′-end of one strand and the 5′ end of therespective other strand forming the duplex structure, the connecting RNAchain is referred to as a “hairpin loop”, “short hairpin RNA” or“shRNA”. Where the two strands are connected covalently by means otherthan an uninterrupted chain of nucleotides between the 3′-end of onestrand and the 5′ end of the respective other strand forming the duplexstructure, the connecting structure is referred to as a “linker”. TheRNA strands may have the same or a different number of nucleotides. Themaximum number of base pairs is the number of nucleotides in theshortest strand of the dsRNA minus any overhangs that are present in theduplex. In addition to the duplex structure, a dsRNA may comprise one ormore nucleotide overhangs. In addition, as used herein, “dsRNA” mayinclude chemical modifications to ribonucleotides, intemucleosidelinkages, end-groups, caps, and conjugated moieties, includingsubstantial modifications at multiple nucleotides and including alltypes of modifications disclosed herein or known in the art. Any suchmodifications, as used in an siRNA- or DsiRNA-type molecule, areencompassed by “dsRNA” for the purposes of this specification andclaims.

The phrase “duplex region” refers to the region in two complementary orsubstantially complementary oligonucleotides that form base pairs withone another, either by Watson-Crick base pairing or other manner thatallows for a duplex between oligonucleotide strands that arecomplementary or substantially complementary. For example, anoligonucleotide strand having 21 nucleotide units can base pair withanother oligonucleotide of 21 nucleotide units, yet only 19 bases oneach strand are complementary or substantially complementary, such thatthe “duplex region” consists of 19 base pairs. The remaining base pairsmay, for example, exist as 5′ and 3′ overhangs. Further, within theduplex region, 100% complementarity is not required; substantialcomplementarity is allowable within a duplex region. Substantialcomplementarity refers to complementarity between the strands such thatthey are capable of annealing under biological conditions. Techniques toempirically determine if two strands are capable of annealing underbiological conditions are well know in the art. Alternatively, twostrands can be synthesized and added together under biologicalconditions to determine if they anneal to one another.

Single-stranded nucleic acids that base pair over a number of bases aresaid to “hybridize.” Hybridization is typically determined underphysiological or biologically relevant conditions (e.g., intracellular:pH 7.2, 140 mM potassium ion; extracellular pH 7.4, 145 mM sodium ion).Hybridization conditions generally contain a monovalent cation andbiologically acceptable buffer and may or may not contain a divalentcation, complex anions, e.g. gluconate from potassium gluconate,uncharged species such as sucrose, and inert polymers to reduce theactivity of water in the sample, e.g. PEG. Such conditions includeconditions under which base pairs can form.

Hybridization is measured by the temperature required to dissociatesingle stranded nucleic acids forming a duplex, i.e., (the meltingtemperature; Tm). Hybridization conditions are also conditions underwhich base pairs can form. Various conditions of stringency can be usedto determine hybridization (see, e.g., Wahl, G. M. and S. L. Berger(1987) Methods Enzymol. 152:399; Kimmel, A. R. (1987) Methods Enzymol.152:507). Stringent temperature conditions will ordinarily includetemperatures of at least about 30° C., more preferably of at least about37° C., and most preferably of at least about 42° C. The hybridizationtemperature for hybrids anticipated to be less than 50 base pairs inlength should be 5-10° C. less than the melting temperature (Tm) of thehybrid, where Tm is determined according to the following equations. Forhybrids less than 18 base pairs in length, Tm(° C.)=2(# of A+Tbases)+4(# of G+C bases). For hybrids between 18 and 49 base pairs inlength, Tm(° C.)=81.5+16.6(log 10[Na+])+0.41 (% G+C)−(600/N), where N isthe number of bases in the hybrid, and [Na+] is the concentration ofsodium ions in the hybridization buffer ([Na+] for 1×SSC=0.165 M). Forexample, a hybridization determination buffer is shown in Table 1.

TABLE 1 To make 50 mL final conc. Vender Cat# Lot# m.w./Stock solutionNaCl 100 mM Sigma S-5150 41K8934 5M 1 mL KCl 80 mM Sigma P-9541 70K0002 74.55 0.298 g MgCl₂ 8 mM Sigma M-1028 120K8933 1M 0.4 mL sucrose 2% w/vFisher BP220- 907105 342.3 1 g 212 Tris-HCl 16 mM Fisher BP1757-  124191M 0.8 mL 500 NaH₂PO₄ 1 mM Sigma S-3193 52H- 120.0 0.006 g 029515 EDTA0.02 mM Sigma E-7889 110K89271 0.5M   2 μL H₂O Sigma W-4502 51K2359 to50 mL pH = 7.0 adjust with at 20° C. HCl

Useful variations on hybridization conditions will be readily apparentto those skilled in the art. Hybridization techniques are well known tothose skilled in the art and are described, for example, in Benton andDavis (Science 196:180, 1977); Grunstein and Hogness (Proc. Natl. Acad.Sci., USA 72:3961, 1975); Ausubel et al. (Current Protocols in MolecularBiology, Wiley Interscience, New York, 2001); Berger and Kimmel(Antisense to Molecular Cloning Techniques, 1987, Academic Press, NewYork); and Sambrook et al., Molecular Cloning: A Laboratory Manual, ColdSpring Harbor Laboratory Press, New York.

As used herein, “oligonucleotide strand” is a single stranded nucleicacid molecule.

An oligonucleotide may comprise ribonucleotides, deoxyribonucleotides,modified nucleotides (e.g., nucleotides with 2′ modifications, syntheticbase analogs, etc.) or combinations thereof. Such modifiedoligonucleotides can be preferred over native forms because ofproperties such as, for example, enhanced cellular uptake and increasedstability in the presence of nucleases.

As used herein, the term “ribonucleotide” encompasses natural andsynthetic, unmodified and modified ribonucleotides. Modificationsinclude changes to the sugar moiety, to the base moiety and/or to thelinkages between ribonucleotides in the oligonucleotide. As used herein,the term “ribonucleotide” specifically excludes a deoxyribonucleotide,which is a nucleotide possessing a single proton group at the 2′ ribosering position.

As used herein, the term “deoxyribonucleotide” encompasses natural andsynthetic, unmodified and modified deoxyribonucleotides. Modificationsinclude changes to the sugar moiety, to the base moiety and/or to thelinkages between deoxyribonucleotide in the oligonucleotide. As usedherein, the term “deoxyribonucleotide” also includes a modifiedribonucleotide that does not permit Dicer cleavage of a dsRNA agent,e.g., a 2′-O-methyl ribonucleotide, a phosphorothioate-modifiedribonucleotide residue, etc., that does not permit Dicer cleavage tooccur at a bond of such a residue.

As used herein, the term “PS-NA” refers to a phosphorothioate-modifiednucleotide residue. The term “PS-NA” therefore encompasses bothphosphorothioate-modified ribonucleotides (“PS-RNAs”) andphosphorothioate-modified deoxyribonucleotides (“PS-DNAs”).

As used herein, “Dicer” refers to an endoribonuclease in the RNase IIIfamily that cleaves a dsRNA or dsRNA-containing molecule, e.g.,double-stranded RNA (dsRNA) or pre-microRNA (miRNA), intodouble-stranded nucleic acid fragments 19-25 nucleotides long, usuallywith a two-base overhang on the 3′ end. With respect to certain dsRNAsof the invention (e.g., “DsiRNAs”), the duplex formed by a dsRNA regionof an agent of the invention is recognized by Dicer and is a Dicersubstrate on at least one strand of the duplex. Dicer catalyzes thefirst step in the RNA interference pathway, which consequently resultsin the degradation of a target RNA. The protein sequence of human Diceris provided at the NCBI database under accession number NP 085124,hereby incorporated by reference.

Dicer “cleavage” can be determined as follows (e.g., see Collingwood etal., Oligonucleotides 18:187-200 (2008)). In a Dicer cleavage assay, RNAduplexes (100 pmol) are incubated in 20 μL of 20 mM Tris pH 8.0, 200 mMNaCl, 2.5 mM MgCl2 with or without 1 unit of recombinant human Dicer(Stratagene, La Jolla, Calif.) at 37° C. for 18-24 hours. Samples aredesalted using a Performa SR 96-well plate (Edge Biosystems,Gaithersburg, Md.). Electrospray-ionization liquid chromatography massspectroscopy (ESI-LCMS) of duplex RNAs pre- and post-treatment withDicer is done using an Oligo HTCS system (Novatia, Princeton, N.J.; Hailet al., 2004), which consists of a ThermoFinnigan TSQ7000, Xcalibur datasystem, ProMass data processing software and Paradigm MS4 HPLC (MichromBioResources, Auburn, Calif.). In this assay, Dicer cleavage occurswhere at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, oreven 100% of the Dicer substrate dsRNA, (i.e., 25-30 bp, dsRNA,preferably 26-30 bp dsRNA) is cleaved to a shorter dsRNA (e.g., 19-23 bpdsRNA, preferably, 21-23 bp dsRNA).

As used herein, “Dicer cleavage site” refers to the sites at which Dicercleaves a dsRNA (e.g., the dsRNA region of a DsiRNA agent of theinvention). Dicer contains two RNase III domains which typically cleaveboth the sense and antisense strands of a dsRNA. The average distancebetween the RNase III domains and the PAZ domain determines the lengthof the short double-stranded nucleic acid fragments it produces and thisdistance can vary (Macrae et al. (2006) Science 311: 195-8). As shown inFIG. 1, Dicer is projected to cleave certain double-stranded ribonucleicacids of the instant invention that possess an antisense strand having a2 nucleotide 3′ overhang at a site between the 21^(st) and 22^(nd)nucleotides removed from the 3′ terminus of the antisense strand, and ata corresponding site between the 21^(st) and 22^(nd) nucleotides removedfrom the 5′ terminus of the sense strand. The projected and/or prevalentDicer cleavage site(s) for dsRNA molecules distinct from those depictedin FIG. 1 may be similarly identified via art-recognized methods,including those described in Macrae et al. While the Dicer cleavageevents depicted in FIG. 1 generate 21 nucleotide siRNAs, it is notedthat Dicer cleavage of a dsRNA (e.g., DsiRNA) can result in generationof Dicer-processed siRNA lengths of 19 to 23 nucleotides in length.Indeed, in certain embodiments, a double-stranded DNA region may beincluded within a dsRNA for purpose of directing prevalent Dicerexcision of a typically non-preferred 19 mer or 20 mer siRNA, ratherthan a 21 mer.

As used herein, “overhang” refers to unpaired nucleotides, in thecontext of a duplex having one or more free ends at the 5′ terminus or3′ terminus of a dsRNA. In certain embodiments, the overhang is a 3′ or5′ overhang on the antisense strand or sense strand. In someembodiments, the overhang is a 3′ overhang having a length of betweenone and six nucleotides, optionally one to five, one to four, one tothree, one to two, two to six, two to five, two to four, two to three,three to six, three to five, three to four, four to six, four to five,five to six nucleotides, or one, two, three, four, five or sixnucleotides. “Blunt” or “blunt end” means that there are no unpairednucleotides at that end of the dsRNA, i.e., no nucleotide overhang. Forclarity, chemical caps or non-nucleotide chemical moieties conjugated tothe 3′ end or 5′ end of an siRNA are not considered in determiningwhether an siRNA has an overhang or is blunt ended. In certainembodiments, the invention provides a dsRNA molecule for inhibiting theexpression of the transthyretin target gene in a cell or mammal, whereinthe dsRNA comprises an antisense strand comprising a region ofcomplementarity which is complementary to at least a part of an mRNAformed in the expression of the transthyretin target gene, and whereinthe region of complementarity is less than 35 nucleotides in length,optionally 19-24 nucleotides in length or 25-30 nucleotides in length,and wherein the dsRNA, upon contact with a cell expressing thetransthyretin target gene, inhibits the expression of the transthyretintarget gene by at least 10%, 25%, or 40%.

A dsRNA of the invention comprises two RNA strands that are sufficientlycomplementary to hybridize to form a duplex structure. One strand of thedsRNA (the antisense strand) comprises a region of complementarity thatis substantially complementary, and generally fully complementary, to atarget sequence, derived from the sequence of an mRNA formed during theexpression of the transthyretin target gene, the other strand (the sensestrand) comprises a region which is complementary to the antisensestrand, such that the two strands hybridize and form a duplex structurewhen combined under suitable conditions. Generally, the duplex structureis between 15 and 35, optionally between 25 and 30, between 26 and 30,between 18 and 25, between 19 and 24, or between 19 and 21 base pairs inlength. Similarly, the region of complementarity to the target sequenceis between 15 and 35, optionally between 18 and 30, between 25 and 30,between 19 and 24, or between 19 and 21 nucleotides in length. The dsRNAof the invention may further comprise one or more single-strandednucleotide overhang(s). It has been identified that dsRNAs comprisingduplex structures of between 15 and 35 base pairs in length can beeffective in inducing RNA interference, including DsiRNAs (generally ofat least 25 base pairs in length) and siRNAs (in certain embodiments,duplex structures of siRNAs are between 20 and 23, and optionally,specifically 21 base pairs (Elbashir et al., EMBO 20: 6877-6888)). Ithas also been identified that dsRNAs possessing duplexes shorter than 20base pairs can be effective as well (e.g., 15, 16, 17, 18 or 19 basepair duplexes). In certain embodiments, the dsRNAs of the invention cancomprise at least one strand of a length of 19 nucleotides or more. Incertain embodiments, it can be reasonably expected that shorter dsRNAscomprising a sequence complementary to one of the sequences of Table 4,minus only a few nucleotides on one or both ends may be similarlyeffective as compared to the dsRNAs described above and in Tables 2-3and 5. Hence, dsRNAs comprising a partial sequence of at least 15, 16,17, 18, 19, 20, or more contiguous nucleotides sufficientlycomplementary to one of the sequences of Table 4, and differing in theirability to inhibit the expression of the transthyretin target gene in anassay as described herein by not more than 5, 10, 15, 20, 25, or 30%inhibition from a dsRNA comprising the full sequence, are contemplatedby the invention. In one embodiment, at least one end of the dsRNA has asingle-stranded nucleotide overhang of 1 to 5, optionally 1 to 4, incertain embodiments, 1 or 2 nucleotides. Certain dsRNA structures havingat least one nucleotide overhang possess superior inhibitory propertiesas compared to counterparts possessing base-paired blunt ends at bothends of the dsRNA molecule.

As used herein, the term “RNA processing” refers to processingactivities performed by components of the siRNA, miRNA or RNase Hpathways (e.g., Drosha, Dicer, Argonaute2 or other RISCendoribonucleases, and RNaseH), which are described in greater detailbelow (see “RNA Processing” section below). The term is explicitlydistinguished from the post-transcriptional processes of 5′ capping ofRNA and degradation of RNA via non-RISC- or non-RNase H-mediatedprocesses. Such “degradation” of an RNA can take several forms, e.g.deadenylation (removal of a 3′ poly(A) tail), and/or nuclease digestionof part or all of the body of the RNA by one or more of several endo- orexo-nucleases (e.g., RNase III, RNase P, RNase T1, RNase A (1, 2, 3,4/5), oligonucleotidase, etc.).

By “homologous sequence” is meant a nucleotide sequence that is sharedby one or more polynucleotide sequences, such as genes, gene transcriptsand/or non-coding polynucleotides. For example, a homologous sequencecan be a nucleotide sequence that is shared by two or more genesencoding related but different proteins, such as different members of agene family, different protein epitopes, different protein isoforms orcompletely divergent genes, such as a cytokine and its correspondingreceptors. A homologous sequence can be a nucleotide sequence that isshared by two or more non-coding polynucleotides, such as noncoding DNAor RNA, regulatory sequences, introns, and sites of transcriptionalcontrol or regulation. Homologous sequences can also include conservedsequence regions shared by more than one polynucleotide sequence.Homology does not need to be perfect homology (e.g., 100%), as partiallyhomologous sequences are also contemplated by the instant invention(e.g., 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 89%, 88%, 87%,86%, 85%, 84%, 83%, 82%, 81%, 80% etc.). Indeed, design and use of thedsRNA agents of the instant invention contemplates the possibility ofusing such dsRNA agents not only against target RNAs of transthyretinpossessing perfect complementarity with the presently described dsRNAagents, but also against target transthyretin RNAs possessing sequencesthat are, e.g., only 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%,89%, 88%, 87%, 86%, 85%, 84%, 83%, 82%, 81%, 80% etc. complementary tosaid dsRNA agents. Similarly, it is contemplated that the presentlydescribed dsRNA agents of the instant invention might be readily alteredby the skilled artisan to enhance the extent of complementarity betweensaid dsRNA agents and a target transthyretin RNA, e.g., of a specificallelic variant of transthyretin (e.g., an allele of enhancedtherapeutic interest). Indeed, dsRNA agent sequences with insertions,deletions, and single point mutations relative to the targettransthyretin sequence can also be effective for inhibition.Alternatively, dsRNA agent sequences with nucleotide analogsubstitutions or insertions can be effective for inhibition.

Sequence identity may be determined by sequence comparison and alignmentalgorithms known in the art. To determine the percent identity of twonucleic acid sequences (or of two amino acid sequences), the sequencesare aligned for comparison purposes (e.g., gaps can be introduced in thefirst sequence or second sequence for optimal alignment). Thenucleotides (or amino acid residues) at corresponding nucleotide (oramino acid) positions are then compared. When a position in the firstsequence is occupied by the same residue as the corresponding positionin the second sequence, then the molecules are identical at thatposition. The percent identity between the two sequences is a functionof the number of identical positions shared by the sequences (i.e., %homology=# of identical positions/total # of positions×100), optionallypenalizing the score for the number of gaps introduced and/or length ofgaps introduced.

The comparison of sequences and determination of percent identitybetween two sequences can be accomplished using a mathematicalalgorithm. In one embodiment, the alignment generated over a certainportion of the sequence aligned having sufficient identity but not overportions having low degree of identity (i.e., a local alignment). Apreferred, non-limiting example of a local alignment algorithm utilizedfor the comparison of sequences is the algorithm of Karlin and Altschul(1990) Proc. Natl. Acad. Sci. USA 87:2264-68, modified as in Karlin andAltschul (1993) Proc. Natl. Acad. Sci. USA 90:5873-77. Such an algorithmis incorporated into the BLAST programs (version 2.0) of Altschul, etal. (1990) J.

Mol. Biol. 215:403-10.

In another embodiment, a gapped alignment, the alignment is optimized byintroducing appropriate gaps, and percent identity is determined overthe length of the aligned sequences (i.e., a gapped alignment). Toobtain gapped alignments for comparison purposes, Gapped BLAST can beutilized as described in Altschul et al., (1997) Nucleic Acids Res.25(17):3389-3402. In another embodiment, a global alignment thealignment is optimized by introducing appropriate gaps, and percentidentity is determined over the entire length of the sequences aligned.(i.e., a global alignment). A preferred, non-limiting example of amathematical algorithm utilized for the global comparison of sequencesis the algorithm of Myers and Miller, CABIOS (1989). Such an algorithmis incorporated into the ALIGN program (version 2.0) which is part ofthe GCG sequence alignment software package. When utilizing the ALIGNprogram for comparing amino acid sequences, a PAM 120 weight residuetable, a gap length penalty of 12, and a gap penalty of 4 can be used.

Greater than 80% sequence identity, e.g., 80%, 81%, 82%, 83%, 84%, 85%,86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% oreven 100% sequence identity, between the dsRNA antisense strand and theportion of the transthyretin RNA sequence is preferred. Alternatively,the dsRNA may be defined functionally as a nucleotide sequence (oroligonucleotide sequence) that is capable of hybridizing with a portionof the transthyretin RNA (e.g., 400 mM NaCl, 40 mM PIPES pH 6.4, 1 mMEDTA, 50° C. or 70° C. hybridization for 12-16 hours; followed bywashing). Additional preferred hybridization conditions includehybridization at 70° C. in 1×SSC or 50° C. in 1×SSC, 50% formamidefollowed by washing at 70° C. in 0.3×SSC or hybridization at 70° C. in4×SSC or 50° C. in 4×SSC, 50% formamide followed by washing at 67° C. in1×SSC. The hybridization temperature for hybrids anticipated to be lessthan 50 base pairs in length should be 5-10° C. less than the meltingtemperature (Tm) of the hybrid, where Tm is determined according to thefollowing equations. For hybrids less than 18 base pairs in length, Tm(°C.)=2(# of A+T bases)+4(# of G+C bases). For hybrids between 18 and 49base pairs in length, Tm(° C.)=81.5+16.6(log 10[Na+])+0.41 (%G+C)−(600/N), where N is the number of bases in the hybrid, and [Na+] isthe concentration of sodium ions in the hybridization buffer ([Na+] for1×SSC=0.165 M). Additional examples of stringency conditions forpolynucleotide hybridization are provided in Sambrook, J., E. F.Fritsch, and T. Maniatis, 1989, Molecular Cloning: A Laboratory Manual,Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., chapters9 and 11, and Current Protocols in Molecular Biology, 1995, F. M.Ausubel et al., eds., John Wiley & Sons, Inc., sections 2.10 and6.3-6.4. The length of the identical nucleotide sequences may be atleast 10, 12, 15, 17, 20, 22, 25, 27 or 30 bases.

By “conserved sequence region” is meant, a nucleotide sequence of one ormore regions in a polynucleotide does not vary significantly betweengenerations or from one biological system, subject, or organism toanother biological system, subject, or organism.

The polynucleotide can include both coding and non-coding DNA and RNA.

By “sense region” is meant a nucleotide sequence of a dsRNA moleculehaving complementarity to an antisense region of the dsRNA molecule. Inaddition, the sense region of a dsRNA molecule can comprise a nucleicacid sequence having homology with a target nucleic acid sequence.

By “antisense region” is meant a nucleotide sequence of a dsRNA moleculehaving complementarity to a target nucleic acid sequence. In addition,the antisense region of a dsRNA molecule comprises a nucleic acidsequence having complementarity to a sense region of the dsRNA molecule.

As used herein, “antisense strand” refers to a single stranded nucleicacid molecule which has a sequence complementary to that of a targetRNA. When the antisense strand contains modified nucleotides with baseanalogs, it is not necessarily complementary over its entire length, butmust at least hybridize with a target RNA.

As used herein, “sense strand” refers to a single stranded nucleic acidmolecule which has a sequence complementary to that of an antisensestrand. When the antisense strand contains modified nucleotides withbase analogs, the sense strand need not be complementary over the entirelength of the antisense strand, but must at least duplex with theantisense strand.

As used herein, “guide strand” refers to a single stranded nucleic acidmolecule of a dsRNA or dsRNA-containing molecule, which has a sequencesufficiently complementary to that of a target RNA to result in RNAinterference. After cleavage of the dsRNA or dsRNA-containing moleculeby Dicer, a fragment of the guide strand remains associated with RISC,binds a target RNA as a component of the RISC complex, and promotescleavage of a target RNA by RISC. As used herein, the guide strand doesnot necessarily refer to a continuous single stranded nucleic acid andmay comprise a discontinuity, preferably at a site that is cleaved byDicer. A guide strand is an antisense strand.

As used herein, “passenger strand” refers to an oligonucleotide strandof a dsRNA or dsRNA-containing molecule, which has a sequence that iscomplementary to that of the guide strand. As used herein, the passengerstrand does not necessarily refer to a continuous single strandednucleic acid and may comprise a discontinuity, preferably at a site thatis cleaved by Dicer. A passenger strand is a sense strand.

By “target nucleic acid” is meant a nucleic acid sequence whoseexpression, level or activity is to be modulated. The target nucleicacid can be DNA or RNA. For agents that target transthyretin, in certainembodiments, the target nucleic acid is transthyretin RNA, e.g., incertain embodiments, transthyretin mRNA. Transthyretin RNA target sitescan also interchangeably be referenced by corresponding cDNA sequences.Levels of transthyretin may also be targeted via targeting of upstreameffectors of transthyretin, or the effects of modulated or misregulatedtransthyretin may also be modulated by targeting of molecules downstreamof transthyretin in the transthyretin signalling pathway.

By “complementarity” is meant that a nucleic acid can form hydrogenbond(s) with another nucleic acid sequence by either traditionalWatson-Crick or other non-traditional types. In reference to the nucleicmolecules of the present invention, the binding free energy for anucleic acid molecule with its complementary sequence is sufficient toallow the relevant function of the nucleic acid to proceed, e.g., RNAiactivity. Determination of binding free energies for nucleic acidmolecules is well known in the art (see, e.g., Turner et al., 1987, CSHSymp. Quant. Biol. LII pp. 123-133; Frier et al., 1986, Proc. Nat. Acad.Sci. USA 83:9373-9377; Turner et al., 1987, J. Am. Chem. Soc.109:3783-3785). A percent complementarity indicates the percentage ofcontiguous residues in a nucleic acid molecule that can form hydrogenbonds (e.g., Watson-Crick base pairing) with a second nucleic acidsequence (e.g., 5, 6, 7, 8, 9, or 10 nucleotides out of a total of 10nucleotides in the first oligonucleotide being based paired to a secondnucleic acid sequence having 10 nucleotides represents 50%, 60%, 70%,80%, 90%, and 100% complementary respectively). “Perfectlycomplementary” means that all the contiguous residues of a nucleic acidsequence will hydrogen bond with the same number of contiguous residuesin a second nucleic acid sequence. In one embodiment, a dsRNA moleculeof the invention comprises 19 to 30 (e.g., 19, 20, 21, 22, 23, 24, 25,26, 27, 28, 29, or 30 or more) nucleotides that are complementary to oneor more target nucleic acid molecules or a portion thereof.

As used herein, a dsNA, e.g., DsiRNA or siRNA, having a sequence“sufficiently complementary” to a target RNA or cDNA sequence (e.g.,transthyretin mRNA) means that the dsNA has a sequence sufficient totrigger the destruction of the target RNA (where a cDNA sequence isrecited, the RNA sequence corresponding to the recited cDNA sequence) bythe RNAi machinery (e.g., the RISC complex) or process. For example, adsNA that is “sufficiently complementary” to a target RNA or cDNAsequence to trigger the destruction of the target RNA by the RNAimachinery or process can be identified as a dsNA that causes adetectable reduction in the level of the target RNA in an appropriateassay of dsNA activity (e.g., an in vitro assay as described in Example2 below), or, in further examples, a dsNA that is sufficientlycomplementary to a target RNA or cDNA sequence to trigger thedestruction of the target RNA by the RNAi machinery or process can beidentified as a dsNA that produces at least a 5%, at least a 10%, atleast a 15%, at least a 20%, at least a 25%, at least a 30%, at least a35%, at least a 40%, at least a 45%, at least a 50%, at least a 55%, atleast a 60%, at least a 65%, at least a 70%, at least a 75%, at least a80%, at least a 85%, at least a 90%, at least a 95%, at least a 98% orat least a 99% reduction in the level of the target RNA in anappropriate assay of dsNA activity. In additional examples, a dsNA thatis sufficiently complementary to a target RNA or cDNA sequence totrigger the destruction of the target RNA by the RNAi machinery orprocess can be identified based upon assessment of the duration of acertain level of inhibitory activity with respect to the target RNA orprotein levels in a cell or organism. For example, a dsNA that issufficiently complementary to a target RNA or cDNA sequence to triggerthe destruction of the target RNA by the RNAi machinery or process canbe identified as a dsNA capable of reducing target mRNA levels by atleast 20% at least 48 hours post-administration of said dsNA to a cellor organism. Preferably, a dsNA that is sufficiently complementary to atarget RNA or cDNA sequence to trigger the destruction of the target RNAby the RNAi machinery or process is identified as a dsNA capable ofreducing target mRNA levels by at least 40% at least 72 hourspost-administration of said dsNA to a cell or organism, by at least 40%at least four, five or seven days post-administration of said dsNA to acell or organism, by at least 50% at least 48 hours post-administrationof said dsNA to a cell or organism, by at least 50% at least 72 hourspost-administration of said dsNA to a cell or organism, by at least 50%at least four, five or seven days post-administration of said dsNA to acell or organism, by at least 80% at least 48 hours post-administrationof said dsNA to a cell or organism, by at least 80% at least 72 hourspost-administration of said dsNA to a cell or organism, or by at least80% at least four, five or seven days post-administration of said dsNAto a cell or organism.

In certain embodiments, a nucleic acid of the invention (e.g., a DsiRNAor siRNA) possesses a sequence “sufficiently complementary to hybridize”to a target RNA or cDNA sequence, thereby achieving an inhibitory effectupon the target RNA. Hybridization, and conditions available fordetermining whether one nucleic acid is sufficiently complementary toanother nucleic acid to allow the two sequences to hybridize, isdescribed in greater detail below.

As will be clear to one of ordinary skill in the art, “sufficientlycomplementary” (contrasted with, e.g., “100% complementary”) allows forone or more mismatches to exist between a dsNA of the invention and thetarget RNA or cDNA sequence (e.g., transthyretin mRNA), provided thatthe dsNA possesses complementarity sufficient to trigger the destructionof the target RNA by the RNAi machinery (e.g., the RISC complex) orprocess. In certain embodiments, a “sufficiently complementary” dsNA ofthe invention can harbor one, two, three or even four or more mismatchesbetween the dsNA sequence and the target RNA or cDNA sequence (e.g., incertain such embodiments, the antisense strand of the dsRNA harbors one,two, three, four, five or even six or more mismatches when aligned withthe target RNA or cDNA sequence for maximum complementarity). Additionalconsideration of the preferred location of such mismatches withincertain dsRNAs of the instant invention is considered in greater detailbelow.

In one embodiment, dsRNA molecules of the invention that down regulateor reduce transthyretin gene expression are used for treating,preventing or reducing transthyretin-related diseases or disorders(e.g., cancer) in a subject or organism.

In one embodiment of the present invention, each sequence of a DsiRNAmolecule of the invention is independently 25 to 35 nucleotides inlength, in specific embodiments 25, 26, 27, 28, 29, 30, 31, 32, 33, 34or 35 nucleotides in length. In another embodiment, the DsiRNA duplexesof the invention independently comprise 25 to 30 base pairs (e.g., 25,26, 27, 28, 29, or 30). In another embodiment, one or more strands ofthe DsiRNA molecule of the invention independently comprises 19 to 35nucleotides (e.g., 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31,32, 33, 34 or 35) that are complementary to a target (transthyretin)nucleic acid molecule. In certain embodiments, a DsiRNA molecule of theinvention possesses a length of duplexed nucleotides between 25 and 66nucleotides, optionally between 25 and 49 nucleotides in length (e.g.,25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42,43, 44, 45, 46, 47, 48 or 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59,60, 61, 62, 63, 64, 65, 66 nucleotides in length; optionally, all suchnucleotides base pair with cognate nucleotides of the opposite strand).In related embodiments, a dsNA of the invention possesses strand lengthsthat are, independently, between 19 and 66 nucleotides in length,optionally between 25 and 53 nucleotides in length, e.g., 19, 20, 21,22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39,40, 41, 42, 43, 44, 45, 46, 47, 48 or 49, 50, 51, 52, 53, 54, 55, 56,57, 58, 59, 60, 61, 62, 63, 64, 65, 66 nucleotides in length. In certainembodiments, one strand length is 19-35 nucleotides in length, while theother strand length is 30-66 nucleotides in length and at least onestrand has a 5′ overhang of at least 5 nucleotides in length relative tothe other strand. In certain related embodiments, the 3′ end of thefirst strand and the 5′ end of the second strand form a structure thatis a blunt end or a 1-6 nucleotide 3′ overhang, while the 5′ end of thefirst strand forms a 5-35 nucleotide overhang with respect to the 3′ endof the second strand. Optionally, between one and all nucleotides of the5-35 nucleotide overhang are modified nucleotides (optionally,deoxyribonucleotides and/or modified ribonucleotides).

In some embodiments, a dsNA of the invention has a first or secondstrand that has at least 8 contiguous ribonucleotides. In certainembodiments, a dsNA of the invention has 9, 10, 11, 12, 13, 14, 15, 16,17, 18, 19, 20, 21, 22, 23 or more (e.g., 24, 25, 26, 27, 28, 29, 30,31, 32, 33, 34, 35, 26, or more, up to the full length of the strand)ribonucleotides, optionally including modified ribonucleotides(2′-O-methyl ribonucleotides, phosphorothioate linkages, etc.). Incertain embodiments, the ribonucleotides or modified ribonucleotides arecontiguous.

In certain embodiments of the invention, tetraloop- and modifiednucleotide-containing dsNAs are contemplated as described, e.g., in US2011/0288147. In certain such embodiments, a dsNA of the inventionpossesses a first strand and a second strand, where the first strand andthe second strand form a duplex region of 19-25 nucleotides in length,wherein the first strand comprises a 3′ region that extends beyond thefirst strand-second strand duplex region and comprises a tetraloop, andthe dsNA comprises a discontinuity between the 3′ terminus of the firststrand and the 5′ terminus of the second strand. Optionally, thediscontinuity is positioned at a projected dicer cleavage site of thetetraloop-containing dsNA.

In certain embodiments, a dsNA comprising a first strand and a secondstrand, each strand, independently, having a 5′ terminus and a 3′terminus, and having, independently, respective strand lengths of 25-53nucleotides in length, is sufficiently highly modified (e.g., at least10% or more, at least 20% or more, at least 30% or more, at least 40% ormore, at least 50% or more, at least 60% or more, at least 70% or more,at least 80% or more, at least 90% or more, at least 95% or moreresidues of one and/or both strands are modified such that dicercleavage of the dsNA is prevented (optionally, modified residues occurat and/or flanking one or all predicted dicer cleavage sites of thedsNA). Such non-dicer-cleaved dsNAs retain LDH inhibition activity andare optionally cleaved by non-dicer nucleases to yield, e.g., 15-30, orin particular embodiments, 19-23 nucleotide strand length dsNAs capableof inhibiting LDH in a mammalian cell. In certain related embodiments,dsNAs possessing sufficiently extensive modification to block dicercleavage of such dsNAs optionally possess regions of unmodifiednucleotide residues (e.g., one or two or more consecutive nucleotides,forming a “gap” or “window” in a modification pattern) that allow forand/or promote cleavage of such dsNAs by non-Dicer nucleases. In otherembodiments, Dicer-cleaved dsNAs of the invention can include extensivemodification patterns that possess such “windows” or “gaps” inmodification such that Dicer cleavage preferentially occurs at suchsites (as compared to heavily modified regions within such dsNAs).

In certain additional embodiments of the present invention, eacholigonucleotide of a DsiRNA molecule of the invention is independently25 to 53 nucleotides in length, in specific embodiments 25, 26, 27, 28,29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46,47, 48, 49, 50, 51, 52 or 53 nucleotides in length. For DsiRNAspossessing a strand that exceeds 30 nucleotides in length, availablestructures include those where only one strand exceeds 30 nucleotides inlength (see, e.g., U.S. Pat. No. 8,349,809), or those where both strandsexceed 30 nucleotides in length (see, e.g., WO 2010/080129). Stabilizingmodifications (e.g., 2′-O-Methyl, phosphorothioate,deoxyribonucleotides, including dNTP base pairs, 2′-F, etc.) can beincorporated within any double stranded nucleic acid of the invention,and can be used in particular, and optionally in abundance, especiallywithin DsiRNAs possessing one or both strands exceeding 30 nucleotidesin length. While the guide strand of a double stranded nucleic acid ofthe invention must possess a sequence of, e.g., 15, 16, 17, 18 or 19nucleotides that are complementary to a target RNA (e.g., mRNA),additional sequence(s) of the guide strand need not be complementary tothe target RNA. The end structures of double stranded nucleic acidspossessing at least one strand length in excess of 30 nucleotides canalso be varied while continuing to yield functional dsNAs—e.g. the 5′end of the guide strand and the 3′ end of the passenger strand may forma 5′-overhang, a blunt end or a 3′ overhang (for certain dsNAs, e.g.,“single strand extended” dsNAs, the length of such a 5′ or 3′ overhangcan be 1-4, 1-5, 1-6, 1-10, 1-15, 1-20 or even 1-25 or more); similarly,the 3′ end of the guide strand and the 5′ end of the passenger strandmay form a 5′-overhang, a blunt end or a 3′ overhang (for certain dsNAs,e.g., “single strand extended” dsNAs, the length of such a 5′ or 3′overhang can be 1-4, 1-5, 1-6, 1-10, 1-15, 1-20 or even 1-25 or more).Optionally, such single strand extensions of the dsNAs of the inventioncan be modified, e.g., with phosphorothioate (PS), 2′-F, 2′-O-methyland/or other forms of modification contemplated herein or known in theart, including conjugation to, e.g., GaNAc moieties. In certainembodiments, the length of the passenger strand is 31-49 nucleotideswhile the length of the guide strand is 31-53 nucleotides, optionallywhile the 5′ end of the guide strand forms a blunt end (optionally, abase-paired blunt end) with the 3′ end of the passenger strand,optionally, with the 3′ end of the guide strand and the 5′ end of thepassenger strand forming a 3′ overhang of 1-4 nucleotides in length.Exemplary “extended” Dicer substrate structures are set forth, e.g., inU.S. Pat. Nos. 8,513,207 and 8,349,809, both of which are incorporatedherein by reference. In certain embodiments, one or more strands of thedsNA molecule of the invention independently comprises 19 to 35nucleotides (e.g., 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31,32, 33, 34 or 35) that are complementary to a target (transthyretin)nucleic acid molecule. In certain embodiments, a DsiRNA molecule of theinvention possesses a length of duplexed nucleotides between 25 and 49nucleotides in length (e.g., 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35,36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48 or 49 nucleotides inlength; optionally, all such nucleotides base pair with cognatenucleotides of the opposite strand).

In a further embodiment of the present invention, each oligonucleotideof a DsiRNA molecule of the invention is independently 19 to 66nucleotides in length, in specific embodiments 19, 20, 21, 22, 23, 24,25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42,43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60,61, 62, 63, 64, 65 or 66 nucleotides in length. For dsNAs possessing astrand that exceeds 30 nucleotides in length, available structuresinclude those where only one strand exceeds 30 nucleotides in length(see, e.g., U.S. Pat. No. 8,349,809, where an exemplary double strandednucleic acid possesses a first oligonucleotide strand having a 5′terminus and a 3′ terminus and a second oligonucleotide strand having a5′ terminus and a 3′ terminus, where each of the 5′ termini has a 5′terminal nucleotide and each of the 3′ termini has a 3′ terminalnucleotide, where the first strand (or the second strand) is 25-30nucleotide residues in length, where starting from the 5′ terminalnucleotide (position 1) positions 1 to 23 of the first strand (or thesecond strand) include at least 8 ribonucleotides; the second strand (orthe first strand) is 36-66 nucleotide residues in length and, startingfrom the 3′ terminal nucleotide, includes at least 8 ribonucleotides inthe positions paired with positions 1-23 of the first strand to form aduplex; where at least the 3′ terminal nucleotide of the second strand(or the first strand) is unpaired with the first strand (or the secondstrand), and up to 6 consecutive 3′ terminal nucleotides are unpairedwith the first strand (or the second strand), thereby forming a 3′single stranded overhang of 1-6 nucleotides; where the 5′ terminus ofthe second strand (or the first strand) includes from 10-30 consecutivenucleotides which are unpaired with the first strand (or the secondstrand), thereby forming a 10-30 nucleotide single stranded 5′ overhang;where at least the first strand (or the second strand) 5′ terminal and3′ terminal nucleotides are base paired with nucleotides of the secondstrand (or first strand) when the first and second strands are alignedfor maximum complementarity, thereby forming a substantially duplexedregion between the first and second strands; and the second strand issufficiently complementary to a target RNA along at least 19ribonucleotides of the second strand length to reduce target geneexpression when the double stranded nucleic acid is introduced into amammalian cell), or those where both strands exceed 30 nucleotides inlength (see, e.g., U.S. Pat. No. 8,513,207, where an exemplary doublestranded nucleic acid (dsNA) possesses a first oligonucleotide strandhaving a 5′ terminus and a 3′ terminus and a second oligonucleotidestrand having a 5′ terminus and a 3′ terminus, where the first strand is31 to 49 nucleotide residues in length, where starting from the firstnucleotide (position 1) at the 5′ terminus of the first strand,positions 1 to 23 of the first strand are ribonucleotides; the secondstrand is 31 to 53 nucleotide residues in length and includes 23consecutive ribonucleotides that base pair with the ribonucleotides ofpositions 1 to 23 of the first strand to form a duplex; the 5′ terminusof the first strand and the 3′ terminus of said second strand form ablunt end or a 1-4 nucleotide 3′ overhang; the 3′ terminus of the firststrand and the 5′ terminus of said second strand form a duplexed bluntend, a 5′ overhang or a 3′ overhang; optionally, at least one ofpositions 24 to the 3′ terminal nucleotide residue of the first strandis a deoxyribonucleotide, optionally, that base pairs with adeoxyribonucleotide of said second strand; and the second strand issufficiently complementary to a target RNA along at least 19ribonucleotides of the second strand length to reduce target geneexpression when the double stranded nucleic acid is introduced into amammalian cell).

In certain embodiments, an active dsNA of the invention can possess a 5′overhang of the first strand (optionally, the passenger strand) withrespect to the second strand (optionally, the guide strand) of 2-50nucleotides (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34,35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50) or morein length. In related embodiments, the duplex region formed by the firstand second strands of such a dsNA is 15, 16, 17, 18, 19, 20, 21, 22, 23,24, 25 or more base pairs in length. The 5′ overhang “extended” regionof the first strand is optionally modified at one or more residues(optionally, at alternating residues, all residues, or any otherselection of residues).

In certain embodiments, an active dsNA of the invention can possess a 3′overhang of the first strand (optionally, the passenger strand) withrespect to the second strand (optionally, the guide strand) of 2-50nucleotides (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34,35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50) or morein length. In related embodiments, the duplex region formed by the firstand second strands of such a dsNA is 15, 16, 17, 18, 19, 20, 21, 22, 23,24, 25 or more base pairs in length. The 3′ overhang “extended” regionof the first strand is optionally modified at one or more residues(optionally, at alternating residues, all residues, or any otherselection of residues).

In additional embodiments, an active dsNA of the invention can possess a5′ overhang of the second strand (optionally, the guide strand) withrespect to the first strand (optionally, the passenger strand) of 2-50nucleotides (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34,35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50) or morein length. In related embodiments, the duplex region formed by the firstand second strands of such a dsNA is 15, 16, 17, 18, 19, 20, 21, 22, 23,24, 25 or more base pairs in length. The 5′ overhang “extended” regionof the second strand is optionally modified at one or more residues(optionally, at alternating residues, all residues, or any otherselection of residues).

In further embodiments, an active dsNA of the invention can possess a 3′overhang of the second strand (optionally, the guide strand) withrespect to the first strand (optionally, the passenger strand) of 2-50nucleotides (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34,35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50) or morein length. In related embodiments, the duplex region formed by the firstand second strands of such a dsNA is 15, 16, 17, 18, 19, 20, 21, 22, 23,24, 25 or more base pairs in length. The 3′ overhang “extended” regionof the second strand is optionally modified at one or more residues(optionally, at alternating residues, all residues, or any otherselection of residues).

In another embodiment of the present invention, each sequence of aDsiRNA molecule of the invention is independently 25 to 35 nucleotidesin length, in specific embodiments 25, 26, 27, 28, 29, 30, 31, 32, 33,34 or 35 nucleotides in length. In another embodiment, the DsiRNAduplexes of the invention independently comprise 25 to 30 base pairs(e.g., 25, 26, 27, 28, 29, or 30). In another embodiment, one or morestrands of the DsiRNA molecule of the invention independently comprises19 to 35 nucleotides (e.g., 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29,30, 31, 32, 33, 34 or 35) that are complementary to a target (TTR)nucleic acid molecule. In certain embodiments, a DsiRNA molecule of theinvention possesses a length of duplexed nucleotides between 25 and 34nucleotides in length (e.g., 25, 26, 27, 28, 29, 30, 31, 32, 33 or 34nucleotides in length; optionally, all such nucleotides base pair withcognate nucleotides of the opposite strand). (Exemplary DsiRNA moleculesof the invention are shown in FIG. 1, and below.) In certainembodiments, at least 10%, at least 20%, at least 30%, at least 35%, atleast 40%, at least 45%, at least 50%, at least 55%, at least 60%, atleast 65%, at least 70%, at least 75%, at least 80%, at least 85%, atleast 90%, at least 95% or more of the nucleotide residues of a nucleicacid of the instant invention are modified residues. For a dsNA of theinvention, at least 10%, at least 20%, at least 30%, at least 35%, atleast 40%, at least 45%, at least 50%, at least 55%, at least 60%, atleast 65%, at least 70%, at least 75%, at least 80%, at least 85%, atleast 90%, at least 95% or more of the nucleotide residues of the firststrand are modified residues. Additionally and/or alternatively for adsNA of the invention, at least 10%, at least 20%, at least 30%, atleast 35%, at least 40%, at least 45%, at least 50%, at least 55%, atleast 60%, at least 65%, at least 70%, at least 75%, at least 80%, atleast 85%, at least 90%, at least 95% or more of the nucleotide residuesof the second strand are modified residues. For the dsNAs of theinvention, modifications of both duplex (double-stranded) regions andoverhang (single-stranded) regions are contemplated. Thus, in certainembodiments, at least 10%, at least 20%, at least 30%, at least 35%, atleast 40%, at least 45%, at least 50%, at least 55%, at least 60%, atleast 65%, at least 70%, at least 75%, at least 80%, at least 85%, atleast 90%, at least 95% or more (e.g., all) duplex nucleotide residuesare modified residues. Additionally and/or alternatively, at least 10%,at least 20%, at least 30%, at least 35%, at least 40%, at least 45%, atleast 50%, at least 55%, at least 60%, at least 65%, at least 70%, atleast 75%, at least 80%, at least 85%, at least 90%, at least 95% ormore (e.g., all) overhang nucleotide residues of one or both strands aremodified residues. Optionally, the modifications of the dsNAs of theinvention do not include an inverted abasic (e.g., inverted deoxyabasic) or inverted dT end-protecting group. Alternatively, a dsNA ofthe invention includes a terminal cap moiety (e.g., an inverted deoxyabasic and/or inverted dT end-protecting group). Optionally, such aterminal cap moiety is located at the 5′ end, at the 3′ end, or at boththe 5′ end and the 3′ end of the first strand, of the second strand, orof both first and second strands.

As used herein “cell” is used in its usual biological sense, and doesnot refer to an entire multicellular organism, e.g., specifically doesnot refer to a human. The cell can be present in an organism, e.g.,birds, plants and mammals such as humans, cows, sheep, apes, monkeys,swine, dogs, and cats. The cell can be prokaryotic (e.g., bacterialcell) or eukaryotic (e.g., mammalian or plant cell). The cell can be ofsomatic or germ line origin, totipotent or pluripotent, dividing ornon-dividing. The cell can also be derived from or can comprise a gameteor embryo, a stem cell, or a fully differentiated cell. Within certainaspects, the term “cell” refers specifically to mammalian cells, such ashuman cells, that contain one or more isolated dsRNA molecules of thepresent disclosure. In particular aspects, a cell processes dsRNAs ordsRNA-containing molecules resulting in RNA intereference of targetnucleic acids, and contains proteins and protein complexes required forRNAi, e.g., Dicer and RISC.

In certain embodiments, dsRNAs of the invention are Dicer substratesiRNAs (“DsiRNAs”). DsiRNAs can possess certain advantages as comparedto inhibitory nucleic acids that are not dicer substrates(“non-DsiRNAs”). Such advantages include, but are not limited to,enhanced duration of effect of a DsiRNA relative to a non-DsiRNA, aswell as enhanced inhibitory activity of a DsiRNA as compared to anon-DsiRNA (e.g., a 19-23 mer siRNA) when each inhibitory nucleic acidis suitably formulated and assessed for inhibitory activity in amammalian cell at the same concentration (in this latter scenario, theDsiRNA would be identified as more potent than the non-DsiRNA).Detection of the enhanced potency of a DsiRNA relative to a non-DsiRNAis often most readily achieved at a formulated concentration (e.g.,transfection concentration of the dsRNA) that results in the DsiRNAeliciting approximately 30-70% knockdown activity upon a target RNA(e.g., a mRNA). For active DsiRNAs, such levels of knockdown activityare most often achieved at in vitro mammalian cell DsiRNA transfectionconcentrations of 1 nM or less of as suitably formulated, and in certaininstances are observed at DsiRNA transfection concentrations of 200 pMor less, 100 pM or less, 50 pM or less, 20 pM or less, 10 pM or less, 5pM or less, or even 1 pM or less. Indeed, due to the variability amongDsiRNAs of the precise concentration at which 30-70% knockdown of atarget RNA is observed, construction of an IC₅₀ curve via assessment ofthe inhibitory activity of DsiRNAs and non-DsiRNAs across a range ofeffective concentrations is a preferred method for detecting theenhanced potency of a DsiRNA relative to a non-DsiRNA inhibitory agent.

In certain embodiments, a DsiRNA (in a state as initially formed, priorto dicer cleavage) is more potent at reducing transthyretin target geneexpression in a mammalian cell than a 19, 20, 21, 22 or 23 base pairsequence that is contained within it. In certain such embodiments, aDsiRNA prior to dicer cleavage is more potent than a 19-21 mer containedwithin it. Optionally, a DsiRNA prior to dicer cleavage is more potentthan a 19 base pair duplex contained within it that is synthesized withsymmetric dTdT overhangs (thereby forming a siRNA possessing 21nucleotide strand lengths having dTdT overhangs). In certainembodiments, the DsiRNA is more potent than a 19-23 mer siRNA (e.g., a19 base pair duplex with dTdT overhangs) that targets at least 19nucleotides of the 21 nucleotide target sequence that is recited for aDsiRNA of the invention (without wishing to be bound by theory, theidentity of a such a target site for a DsiRNA is identified viaidentification of the Ago2 cleavage site for the DsiRNA; once the Ago2cleavage site of a DsiRNA is determined for a DsiRNA, identification ofthe Ago2 cleavage site for any other inhibitory dsRNA can be performedand these Ago2 cleavage sites can be aligned, thereby determining thealignment of projected target nucleotide sequences for multiple dsRNAs).In certain related embodiments, the DsiRNA is more potent than a 19-23mer siRNA that targets at least 20 nucleotides of the 21 nucleotidetarget sequence that is recited for a DsiRNA of the invention.Optionally, the DsiRNA is more potent than a 19-23 mer siRNA thattargets the same 21 nucleotide target sequence that is recited for aDsiRNA of the invention. In certain embodiments, the DsiRNA is morepotent than any 21 mer siRNA that targets the same 21 nucleotide targetsequence that is recited for a DsiRNA of the invention. Optionally, theDsiRNA is more potent than any 21 or 22 mer siRNA that targets the same21 nucleotide target sequence that is recited for a DsiRNA of theinvention. In certain embodiments, the DsiRNA is more potent than any21, 22 or 23 mer siRNA that targets the same 21 nucleotide targetsequence that is recited for a DsiRNA of the invention. As noted above,such potency assessments are most effectively performed upon dsRNAs thatare suitably formulated (e.g., formulated with an appropriatetransfection reagent) at a concentration of 1 nM or less. Optionally, anIC₅₀ assessment is performed to evaluate activity across a range ofeffective inhibitory concentrations, thereby allowing for robustcomparison of the relative potencies of dsRNAs so assayed.

The dsRNA molecules of the invention are added directly, or can becomplexed with lipids (e.g., cationic lipids), packaged withinliposomes, or otherwise delivered to target cells or tissues. Thenucleic acid or nucleic acid complexes can be locally administered torelevant tissues ex vivo, or in vivo through direct dermal application,transdermal application, or injection, with or without theirincorporation in biopolymers. In particular embodiments, the nucleicacid molecules of the invention comprise sequences shown in FIG. 1, andthe below exemplary structures. Examples of such nucleic acid moleculesconsist essentially of sequences defined in these figures and exemplarystructures. Furthermore, where such agents are modified in accordancewith the below description of modification patterning of DsiRNA agents,chemically modified forms of constructs described in FIG. 1, and thebelow exemplary structures can be used in all uses described for theDsiRNA agents of FIG. 1, and the below exemplary structures.

In another aspect, the invention provides mammalian cells containing oneor more dsRNA molecules of this invention. The one or more dsRNAmolecules can independently be targeted to the same or different sites.

By “RNA” is meant a molecule comprising at least one, and preferably atleast 4, 8 and 12 ribonucleotide residues. The at least 4, 8 or 12 RNAresidues may be contiguous. By “ribonucleotide” is meant a nucleotidewith a hydroxyl group at the 2′ position of a β-D-ribofuranose moiety.The terms include double-stranded RNA, single-stranded RNA, isolated RNAsuch as partially purified RNA, essentially pure RNA, synthetic RNA,recombinantly produced RNA, as well as altered RNA that differs fromnaturally occurring RNA by the addition, deletion, substitution and/oralteration of one or more nucleotides. Such alterations can includeaddition of non-nucleotide material, such as to the end(s) of the dsRNAor internally, for example at one or more nucleotides of the RNA.Nucleotides in the RNA molecules of the instant invention can alsocomprise non-standard nucleotides, such as non-naturally occurringnucleotides or chemically synthesized nucleotides or deoxynucleotides.

These altered RNAs can be referred to as analogs or analogs ofnaturally-occurring RNA. By “subject” is meant an organism, which is adonor or recipient of explanted cells or the cells themselves. “Subject”also refers to an organism to which the dsRNA agents of the inventioncan be administered. A subject can be a mammal or mammalian cells,including a human or human cells.

The phrase “pharmaceutically acceptable carrier” refers to a carrier forthe administration of a therapeutic agent. Exemplary carriers includesaline, buffered saline, dextrose, water, glycerol, ethanol, andcombinations thereof. For drugs administered orally, pharmaceuticallyacceptable carriers include, but are not limited to pharmaceuticallyacceptable excipients such as inert diluents, disintegrating agents,binding agents, lubricating agents, sweetening agents, flavoring agents,coloring agents and preservatives. Suitable inert diluents includesodium and calcium carbonate, sodium and calcium phosphate, and lactose,while com starch and alginic acid are suitable disintegrating agents.Binding agents may include starch and gelatin, while the lubricatingagent, if present, will generally be magnesium stearate, stearic acid ortalc. If desired, the tablets may be coated with a material such asglyceryl monostearate or glyceryl distearate, to delay absorption in thegastrointestinal tract. The pharmaceutically acceptable carrier of thedisclosed dsRNA compositions may be micellar structures, such as aliposomes, capsids, capsoids, polymeric nanocapsules, or polymericmicrocapsules.

Polymeric nanocapsules or microcapsules facilitate transport and releaseof the encapsulated or bound dsRNA into the cell. They include polymericand monomeric materials, especially including polybutylcyanoacrylate. Asummary of materials and fabrication methods has been published (seeKreuter, 1991). The polymeric materials which are formed from monomericand/or oligomeric precursors in the polymerization/nanoparticlegeneration step, are per se known from the prior art, as are themolecular weights and molecular weight distribution of the polymericmaterial which a person skilled in the field of manufacturingnanoparticles may suitably select in accordance with the usual skill.

Various methodologies of the instant invention include step thatinvolves comparing a value, level, feature, characteristic, property,etc. to a “suitable control”, referred to interchangeably herein as an“appropriate control”. A “suitable control” or “appropriate control” isa control or standard familiar to one of ordinary skill in the artuseful for comparison purposes. In one embodiment, a “suitable control”or “appropriate control” is a value, level, feature, characteristic,property, etc. determined prior to performing an RNAi methodology, asdescribed herein. For example, a transcription rate, mRNA level,translation rate, protein level, biological activity, cellularcharacteristic or property, genotype, phenotype, etc. can be determinedprior to introducing an RNA silencing agent (e.g., DsiRNA) of theinvention into a cell or organism. In another embodiment, a “suitablecontrol” or “appropriate control” is a value, level, feature,characteristic, property, etc. determined in a cell or organism, e.g., acontrol or normal cell or organism, exhibiting, for example, normaltraits. In yet another embodiment, a “suitable control” or “appropriatecontrol” is a predefined value, level, feature, characteristic,property, etc.

The term “in vitro” has its art recognized meaning, e.g., involvingpurified reagents or extracts, e.g., cell extracts. The term “in vivo”also has its art recognized meaning, e.g., involving living cells, e.g.,immortalized cells, primary cells, cell lines, and/or cells in anorganism.

“Treatment”, or “treating” as used herein, is defined as the applicationor administration of a therapeutic agent (e.g., a dsRNA agent or avector or transgene encoding same) to a patient, or application oradministration of a therapeutic agent to an isolated tissue or cell linefrom a patient, who has a disorder with the purpose to cure, heal,alleviate, relieve, alter, remedy, ameliorate, improve or affect thedisease or disorder, or symptoms of the disease or disorder. The term“treatment” or “treating” is also used herein in the context ofadministering agents prophylactically. The term “effective dose” or“effective dosage” is defined as an amount sufficient to achieve or atleast partially achieve the desired effect. The term “therapeuticallyeffective dose” is defined as an amount sufficient to cure or at leastpartially arrest the disease and its complications in a patient alreadysuffering from the disease. The term “patient” includes human and othermammalian subjects that receive either prophylactic or therapeutictreatment.

Structures of Anti-Transthyretin DsiRNA Agents

In certain embodiments, the anti-transthyretin DsiRNA agents of theinvention can have the following structures:

In one such embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “Y” is an overhang domain comprised of 1-4 RNAmonomers that are optionally 2′-O-methyl RNA monomers. In a relatedembodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “Y” is an overhang domain comprised of 1-4 RNA monomersthat are optionally 2′-O-methyl RNA monomers, and “D”=DNA. In oneembodiment, the top strand is the sense strand, and the bottom strand isthe antisense strand. Alternatively, the bottom strand is the sensestrand and the top strand is the antisense strand.

DsiRNAs of the invention can carry a broad range of modificationpatterns (e.g., 2′-O-methyl RNA patterns, e.g., within extended DsiRNAagents). Certain modification patterns of the second strand of DsiRNAsof the invention are presented below.

In one embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. In arelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers, and“D”=DNA. The top strand is the sense strand, and the bottom strand isthe antisense strand.

In another such embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. In arelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand.

In another such embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. In arelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. In arelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. In a further relatedembodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M7” or “M7”modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. In arelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. The top strand is the sense strand, and the bottomstrand is the antisense strand.

In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M6” or “M6”modification pattern.

In other embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In a related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In anotherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M5” or “M5”modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In a related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M4” or “M4”modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In a related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M8” or “M8”modification pattern.

In other embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M3” or “M3”modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In a related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M2” or “M2”modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In a related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M1” or “M1”modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M9” or “M9”modification pattern.

In other embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In a related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M10” or “M10”modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M11” or “M1”modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M12” or “M12”modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M13” or “M13”modification pattern.

In other embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M21” or “M21”modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M14” or “M14”modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M15” or “M15”modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In a related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M16” or “M16”modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M17” or “M17”modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M18” or “M18”modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M19” or “M19”modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M20” or “M20”modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M22” or “M22”modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M24” or “M24”modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M25” or “M25”modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M26” or “M26”modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M27” or “M27”modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M28” or “M28”modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M29” or “M29”modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M30” or “M30”modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M31” or “M31”modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M32” or “M32”modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M34” or “M34”modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M35” or “M35”modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M37” or “M37”modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M38” or “M38”modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M40” or “M40”modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M41” or “M41”modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M36” or “M36”modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M42” or “M42”modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M43” or “M43”modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M44” or “M44”modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M45” or “M45”modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M46” or “M46”modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M47” or “M47”modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M48” or “M48”modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M52” or “M52”modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M54” or “M54”modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M55” or “M55”modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M56” or “M56”modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M57” or “M57”modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M58” or “M58”modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M59” or “M59”modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M60” or “M60”modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M61” or “M61”modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M62” or “M62”modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M63” or “M63”modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M64” or “M64”modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M65” or “M65”modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M66” or “M66”modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M67” or “M67”modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M68” or “M68”modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M69” or “M69”modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M70” or “M70”modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M71” or “M71”modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M72” or “M72”modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M73” or “M73”modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. In a further relatedembodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M7*” or “M7*”modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M6*” or “M6*”modification pattern.

In other embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In anotherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M5*” or “M5*”modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M4*” or “M4*”modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M8*” or “M8*”modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M2*” or “M2*”modification pattern.

In other embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M10*” or“M10*” modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M11*” or“M11*” modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M13*” or“M13*” modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M14*” or“M14*” modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M15*” or“M15*” modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M16*” or“M16*” modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M17*” or“M17*” modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M18*” or“M18*” modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M19*” or“M19*” modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M20*” or“M20*” modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M22*” or“M22*” modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M24*” or“M24*” modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M25*” or“M25*” modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M26*” or“M26*” modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M27*” or“M27*” modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M28*” or“M28*” modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M29*” or“M29*” modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M34*” or“M34*” modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M35*” or“M35*” modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M37*” or“M37*” modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M38*” or“M38*” modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M40*” or“M40*” modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M41*” or“M41*” modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M36*” or“M36*” modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M42*” or“M42*” modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M43*” or“M43*” modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M44*” or“M44*” modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M46*” or“M46*” modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M47*” or“M47*” modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M48*” or“M48*” modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M52*” or“M52*” modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M54*” or“M54*” modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M55*” or“M55*” modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M56*” or“M56*” modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M57*” or“M57*” modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M58*” or“M58*” modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M59*” or“M59*” modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M60*” or“M60*” modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M61*” or“M61*” modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M62*” or“M62*” modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M63*” or“M63*” modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M64*” or“M64*” modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M65*” or“M65*” modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M66*” or“M66*” modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M67*” or“M67*” modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M68*” or“M68*” modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M69*” or“M69*” modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M70*” or“M70*” modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M71*” or“M71*” modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M72*” or“M72*” modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M73*” or“M73*” modification pattern.

Additional exemplary antisense strand modifications include thefollowing:

3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M74”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M75”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M76”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M77”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M78”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M79”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M80”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M81”3′-XpXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M82”3′-XpXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M83”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M84”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M85”3′-FFFXXXXXXXXXXXXXXXXXXXXFFFF-5′ “AS-M88”3′-XXXXFXXXFXFXXXXXXXXXXXXXXXX-5′ “AS-M89”3′-FFFXFXFXFXFXFXFXFXXXXXXFFFF-5′ “AS-M90”3′-FFFXXXXXXXXXXXXXXXXXXXXXXFF-5′ “AS-M91”3′-XXXXXXFXXXXXFXFXXXXXXXXXXXX-5′ “AS-M92”3′-FFFXFXXXXXXXXXXXXXFXXXXXXXX-5′ “AS-M93”3′-FFFXFXFXXXXXFXFXFXFXXXXFFFF-5′ “AS-M94”3′-FFFXFXFXFXFXFXFXFXXXXXXFFFF-5′ “AS-M95”3′-FFFXFXFXFXFXFXFXFXXXXXXFFFpF-5′ “AS-M96”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M210”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M74*”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M75*”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M76*”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M77*”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M78*”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M79*”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M80*”3′-XpXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M82*”3′-XpXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M83*”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M84*”3′-XFFXXXXXXXXXXXXXXXXXXXXFFFF-5′ “AS-M88*”3′-XXXXFXXXFXFXXXXXXXXXXXXXXXX-5′ “AS-M89*”3′-XFFXFXFXFXFXFXFXFXXXXXXFFFF-5′ “AS-M90*”3′-XFFXXXXXXXXXXXXXXXXXXXXXXFF-5′ “AS-M91*”3′-XXXXXXFXXXXXFXFXXXXXXXXXXXX-5′ “AS-M92*”3′-XFFXFXXXXXXXXXXXXXFXXXXXXXX-5′ “AS-M93*”3′-XFFXFXFXXXXXFXFXFXFXXXXFFFF-5′ “AS-M94*”3′-XFFXFXFXFXFXFXFXFXXXXXXFFFF-5′ “AS-M95*”3′-XFFXFXFXFXFXFXFXFXXXXXXFFFpF-5′ “AS-M96*”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M210*”3′-XpXXXXXXXXXXXXXXXXXXXXXXXXXpX-5′ “AS-M101”3′-XpXXXXXXXXXXXXXXXXXXXXXXXXXpX-5′ “AS-M104”3′-XpXXXXXXXXXXXXXXXXXXXXXXXXXpX-5′ “AS-M104*”3′-XpFpXFXFXFXFXFXFXFXFXFXFFXXXpX-5′ “AS-M105”3′-XpFpXFXFXFXFXFXFXFXFXFXFFXXXpX-5′ “AS-M105*”3′-XpXXXXXXXXXXXXXXXXXXXXXXXXXpX-5′ “AS-M106”3′-XpXXXXXXXXXXXXXXXXXXXXXXXXXpX-5′ “AS-M106*”3′-XXpXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M107”3′-XXpXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M107*”3′-ba-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M108” (ba = inverted abasic for F7 stabilization  at 3′ end)3′-ba-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M108*”(ba = inverted abasic for F7 stabilization  at 3′ end)3′-XDXXXXXXXXXXXXXXXXXXXXXXXXX-5′ 3′-XpXXFXFXFXXXXXXXXXXXXXXXXXXpX-5′“AS-M110” 3′-XpXXFXFXFXXXXXXXXXXXXXXXXXXpX-5′ “AS-M110*”3′-XpXXFXFXFXXXXXFXFXFXFXXXXXXpX-5′ “AS-M111”3′-XpXXFXFXFFXXXXXXXXXXFXXXXXXpX-5′ “AS-M112”3′-XpXXFXFXFFXXFXXXXXXXFXXXXXXpX-5′ “AS-M113”3′-XpXXFXFXFFFFFXXXXXXXFXXXXXXpX-5′ “AS-M114”3′-XpXXFXFXFFFFFXXXXXXXFXXFXXXpX-5′ “AS-M115”3′-XpXXFXFXFFFFFXXXXXXXFFFFXXXpX-5′ “AS-M116”3′-XpFXFXFXFXFXFXFXFXFXFXFXFXFpX-5′ “AS-M117”3′-XpXXFXFXFXXXXXFXFXFXFXXXXXXpX-5′ “AS-M111*”3′-XpXXFXFXFFXXXXXXXXXXFXXXXXXpX-5′ “AS-M112*”3′-XpXXFXFXFFXXFXXXXXXXFXXXXXXpX-5′ “AS-M113*”3′-XpXXFXFXFFFFFXXXXXXXFXXXXXXpX-5′ “AS-M114*”3′-XpXXFXFXFFFFFXXXXXXXFXXFXXXpX-5′ “AS-M115*”3′-XpXXFXFXFFFFFXXXXXXXFFFFXXXpX-5′ “AS-M116*”3′-XpFXFXFXFXFXFXFXFXFXFXFXFXFpX-5′ “AS-M117*”3′-XpXXXXXXXXXXXXXXXXXXXXXXXXXpX-5′ “AS-M120”3′-XpXXXXXXXXXXXXXXXXXXXXXXXXXpX-5′ “AS-M121”3′-XpXXXXXXXXXXXXXXXXXXXXXXXXXpX-5′ “AS-M122”3′-XpXXXXXXXXXXXXXXXXXXXXXXXXXpX-5′ “AS-M123”3′-XpXXXXXXXXXXXXXXXXXXXXXXXXXpX-5′ “AS-M124”3′-XpXXXXXXXXXXXXXXXXXXXXXXXXXpX-5′ “AS-M125”3′-XpFpXFXFXFXXXXXFXFXFXFXXXFXFpX-5′ “AS-M126”3′-XpFpXFXFXFXXXXXFXFXFXFXXXFXFpX-5′ “AS-M127”3′-XpFpXFXFXFXFXFXFXFXFXFXFFXXXpX-5′ “AS-M128”3′-XpFpXFXFXFXFXFXFXFXFXFXFFFFFpF-5′ “AS-M129”3′-XpFpXFXFXFXFXFXFXFXFXFXXXFXFpX-5′ “AS-M130”3′-XpFpXFXFXFXFXFXFXFXFXFXFXFXFpX-5′ “AS-M131”3′-XpFpXFXFXFXFXFXFXFXFXFXFXXXXpX-5′ “AS-M132”3′-XpFpXFXFXFXFXFXFXFXFXFXFXXXXpX-5′ “AS-M133”3′-XpFpXFXFXFXFXFXFXFXFXFXFXFFFpF-5′ “AS-M134”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M135”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M136”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M137”3′-XXXFXFXFXXXXXFXFXFXFXXXXXXX-5′ “AS-M138”3′-XXXFXFXFFXXXXXXXXXXFXXXXXXX-5′ “AS-M139”3′-XpXXFXFXFXXXXXFXFXFFFXXXXXXpX-5′ “AS-M140”3′-XpXXFXFXFFXXXFFXFXFFFXXXXXXpX-5′ “AS-M141”3′-XpXXFXFXFXFXFXFXFXFFFXXXXXXpX-5′ “AS-M142”3′-XpXXFXFXFFFFFFFXFXFFFXXXXXXpX-5′ “AS-M143”3′-XpXXFXFXFXFXFXFXFXFpXpFpXXXXXXpX-5′ “AS-M144”3′-XXXXXXXXXXXXXXXXFXXXXXXXXXX-5′ “AS-M145”3′-XXXXXXXXXXXXXXFXXXXXXXXXXXX-5′ “AS-M146”3′-XXXXXXFXXXXXXXXXXXXXXXXXXXX-5′ “AS-M147”3′-XXXXXXXXXXFXXXXXXXXXXXXXXXX-5′ “AS-M148”3′-XXXXXXXXXXXXFXXXXXXXXXXXXXX-5′ “AS-M149”3′-XXXXXXXXXXFXFXXXXXXXXXXXXXX-5′ “AS-M150”3′-XXXXXXXXXXXXFXXXFXXXXXXXXXX-5′ “AS-M151”3′-XXXXXXXXXXFXXXFXXXXXXXXXXXX-5′ “AS-M152”3′-XXXXXXXXFXXXXXXXXXXXXXXXXXX-5′ “AS-M153”3′-XXXXXXXXFXXXXXXXXXXXXXXXXXX-5′ “AS-M154”3′-XXXXXXFXXXXXXXXXXXXXXXXXXXX-5′ “AS-M155”3′-XpXXXXXXXXXXXXXXXXXXXXXXXXXpX-5′ “AS-M156”3′-XpXXXXXXXXXXXXXXXXXXXXXXXXXpX-5′ “AS-M157”3′-XpXXFXFFFFXXXFXXFXXFFXXXXXXpX-5′ “AS-M158”3′-XpXXFXFFFFFFFFXXFXXFFXXXXXXpX-5′ “AS-M159”3′-XpXXFXXXFXXXXXFXFXXFFXXXXXXpX-5′ “AS-M160”3′-XpXXFXXXFXFXFXFXFXXFFXXXXXXpX-5′ “AS-M161”3′-XXXXXXXXFXFXFXXXXXXXXXXXXXX-5′ “AS-M162”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M163”3′-XXXXXXXXDXXXXXXXXXXXXXXXXXX-5′ “AS-M164”3′-XpXXXXXXXXXXXXXXXXXXXXXXXXXpX-5′ “AS-M120*”3′-XpXXXXXXXXXXXXXXXXXXXXXXXXXpX-5′ “AS-M121*”3′-XpXXXXXXXXXXXXXXXXXXXXXXXXXpX-5′ “AS-M122*”3′-XpXXXXXXXXXXXXXXXXXXXXXXXXXpX-5′ “AS-M123*”3′-XpXXXXXXXXXXXXXXXXXXXXXXXXXpX-5′ “AS-M124*”3′-XpXXXXXXXXXXXXXXXXXXXXXXXXXpX-5′ “AS-M125*”3′-XpFpXFXFXFXXXXXFXFXFXFXXXFXFpX-5′ “AS-M126*”3′-XpFpXFXFXFXXXXXFXFXFXFXXXFXFpX-5′ “AS-M127*”3′-XpFpXFXFXFXFXFXFXFXFXFXFFXXXpX-5′ “AS-M128*”3′-XpFpXFXFXFXFXFXFXFXFXFXFFFFFpF-5′ “AS-M129*”3′-XpFpXFXFXFXFXFXFXFXFXFXXXFXFpX-5′ “AS-M130*”3′-XpFpXFXFXFXFXFXFXFXFXFXFXFXFpX-5′ “AS-M131*”3′-XpFpXFXFXFXFXFXFXFXFXFXFXXXXpX-5′ “AS-M132*”3′-XpFpXFXFXFXFXFXFXFXFXFXFXXXXpX-5′ “AS-M133*”3′-XpFpXFXFXFXFXFXFXFXFXFXFXFFFpF-5′ “AS-M134*”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M135*”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M136*”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M137*”3′-XXXFXFXFXXXXXFXFXFXFXXXXXXX-5′ “AS-M138*”3′-XXXFXFXFFXXXXXXXXXXFXXXXXXX-5′ “AS-M139*”3′-XpXXFXFXFXXXXXFXFXFFFXXXXXXpX-5′ “AS-M140*”3′-XpXXFXFXFFXXXFFXFXFFFXXXXXXpX-5′ “AS-M141*”3′-XpXXFXFXFXFXFXFXFXFFFXXXXXXpX-5′ “AS-M142*”3′-XpXXFXFXFFFFFFFXFXFFFXXXXXXpX-5′ “AS-M143*”3′-XpXXFXFXFXFXFXFXFXFpXpFpXXXXXXpX-5′ “AS-M144*”3′-XXXXXXXXXXXXXXXXFXXXXXXXXXX-5′ “AS-M145*”3′-XXXXXXXXXXXXXXFXXXXXXXXXXXX-5′ “AS-M146*”3′-XXXXXXFXXXXXXXXXXXXXXXXXXXX-5′ “AS-M147*”3′-XXXXXXXXXXFXXXXXXXXXXXXXXXX-5′ “AS-M148*”3′-XXXXXXXXXXXXFXXXXXXXXXXXXXX-5′ “AS-M149*”3′-XXXXXXXXXXFXFXXXXXXXXXXXXXX-5′ “AS-M150*”3′-XXXXXXXXXXXXFXXXFXXXXXXXXXX-5′ “AS-M151*”3′-XXXXXXXXXXFXXXFXXXXXXXXXXXX-5′ “AS-M152*”3′-XXXXXXXXFXXXXXXXXXXXXXXXXXX-5′ “AS-M153*”3′-XXXXXXXXFXXXXXXXXXXXXXXXXXX-5′ “AS-M154*”3′-XXXXXXFXXXXXXXXXXXXXXXXXXXX-5′ “AS-M155*”3′-XpXXXXXXXXXXXXXXXXXXXXXXXXXpX-5′ “AS-M156*”3′-XpXXXXXXXXXXXXXXXXXXXXXXXXXpX-5′ “AS-M157*”3′-XpXXFXFFFFXXXFXXFXXFFXXXXXXpX-5′ “AS-M158*”3′-XpXXFXFFFFFFFFXXFXXFFXXXXXXpX-5′ “AS-M159*”3′-XpXXFXXXFXXXXXFXFXXFFXXXXXXpX-5′ “AS-M160*”3′-XpXXFXXXFXFXFXFXFXXFFXXXXXXpX-5′ “AS-M161*”3′-XXXXXXXXFXFXFXXXXXXXXXXXXXX-5′ “AS-M162*”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M163*”3′-XXXXXXXXDXXXXXXXXXXXXXXXXXX-5′ “AS-M164*”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M211”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M212”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M215”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M216”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M217”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M218”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M219”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M220”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M221”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M222”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M223”3′-XXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M224”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M225”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M226”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M230”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M231”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M232”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M233”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M234”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M235”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M236”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M237”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M238”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M239”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M240”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M241”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M242”3′-XpXXXXXXXXXXXXXXXXXXXXXXXXXpX-5′ “AS-M243”3′-XpXXXXXXXXXXXXXXXXXXXXXXXXXpX-5′ “AS-M244”3′-XpXXXXXXXXXXXXXXXXXXXXXXXXXpX-5′ “AS-M245”3′-XpXXXXXXXXXXXXXXXXXXXXXXXXXpX-5′ “AS-M246”3′-XpXXXXXXXXXXXXXXXXXXXXXXXXXpX-5′ “AS-M247”3′-XpXXXXXXXXXXXXXXXXXXXXXXXXXpX-5′ “AS-M248”3′-XpXXXXXXXXXXXXXXXXXXXXXXXXXpX-5′ “AS-M249”3′-XpXXXXXXXXXXXXXXXXXXXXXXXXXpX-5′ “AS-M250”3′-XpXXXXXXXXXXXXXXXXXXXXXXXXXpX-5′ “AS-M251”3′-XpXXXXXXXXXXXXXXXXXXXXXXXXXpX-5′ “AS-M252”3′-XpXXXXXXXXXXXXXXXXXXXXXXXXXpX-5′ “AS-M253”3′-XpXXXXXXXXXXXXXXXXXXXXXXXXXpX-5′ “AS-M254”3′-XpXXXXXXXXXXXXXXXXXXXXXXXXXpX-5′ “AS-M255”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M211*”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M212*”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M215*”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M216*”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M217*”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M218*”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M219*”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M220*”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M221*”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M222*”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M223*”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M224*”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M225*”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M226*”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M230*”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M231*”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M232*”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M233*”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M234*”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M235*”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M236*”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M237*”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M238*”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M239*”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M240*”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M241*”3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ “AS-M242*”3′-XpXXXXXXXXXXXXXXXXXXXXXXXXXpX-5′ “AS-M243*”3′-XpXXXXXXXXXXXXXXXXXXXXXXXXXpX-5′ “AS-M244*”3′-XpXXXXXXXXXXXXXXXXXXXXXXXXXpX-5′ “AS-M245*”3′-XpXXXXXXXXXXXXXXXXXXXXXXXXXpX-5′ “AS-M246*”3′-XpXXXXXXXXXXXXXXXXXXXXXXXXXpX-5′ “AS-M247*”3′-XpXXXXXXXXXXXXXXXXXXXXXXXXXpX-5′ “AS-M248*”3′-XpXXXXXXXXXXXXXXXXXXXXXXXXXpX-5′ “AS-M249*”3′-XpXXXXXXXXXXXXXXXXXXXXXXXXXpX-5′ “AS-M250*”3′-XpXXXXXXXXXXXXXXXXXXXXXXXXXpX-5′ “AS-M251*”3′-XpXXXXXXXXXXXXXXXXXXXXXXXXXpX-5′ “AS-M252*”3′-XpXXXXXXXXXXXXXXXXXXXXXXXXXpX-5′ “AS-M253*”3′-XpXXXXXXXXXXXXXXXXXXXXXXXXXpX-5′ “AS-M254*”3′-XpXXXXXXXXXXXXXXXXXXXXXXXXXpX-5′ “AS-M255*”where “X”=RNA, “X”=2′-O-methyl RNA, “D”=DNA, “F”=2′-Fluoro NA and“p”=Phosphorothioate linkage.In certain additional embodiments, the antisense strand of selecteddsRNAs of the invention are extended, optionally at the 5′ end, with anexemplary 5′ extension of base “AS-M8”, “AS-M17” and “AS-M48”modification patterns respectively represented as follows:

(SEQ ID NO: 3478) 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXXU

GCU

UCGT-5′ “AS-M8, extended” (SEQ ID NO: 3478)3′-XXXXXXXXXXXXXXXXXXXXXXXXXXXU

GCU

UCGT-5′ “AS-M17, extended” (SEQ ID NO: 3478)3′-XXXXXXXXXXXXXXXXXXXXXXXXXXXU

GCU

UCGT-5′ “AS-M48, extended”where “X”=RNA; “X”=2′-O-methyl RNA; “F”=2′-Fluoro NA and “A” in bold,italics indicates a 2′-Fluoro-adenine residue.

In certain embodiments, the sense strand of a DsiRNA of the invention ismodified—specific exemplary forms of sense strand modifications areshown below, and it is contemplated that such modified sense strands canbe substituted for the sense strand of any of the DsiRNAs shown above togenerate a DsiRNA comprising a below-depicted sense strand that annealswith an above-depicted antisense strand. Exemplary sense strandmodification patterns include:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM1” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′“SM2” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM3”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM4” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′“SM5” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM6”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM7” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′“SM8” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM9”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM10” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′“SM11” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM12”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM13” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′“SM14” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM15”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM16” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′“SM17” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM18”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM19” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′“SM20” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM21”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM23” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′“SM24” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM25”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM30” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′“SM31” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM32”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM33” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′“SM34” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM35”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM36” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′“SM37” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM38”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM39” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′“SM40” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM41”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM42” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′“SM43” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM44”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM45”, “SM47”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM46” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′“SM48” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM49”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM50” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′“SM51” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM52”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM53” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′“SM54” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM55”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM56” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′“SM57” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM58”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM59” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′“SM60” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM61”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM62” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′“SM63” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM64”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM65” 5′-XXXXXXXXXXXXXXXXXXXXXXXpDpD-3′“SM66” 5′-XpXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM67”5′-XpXXXXXXXXXXXXXXXXXXXXXXpDpD-3′ “SM68”5′-DXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM69”5′-DpXXXXXXXXXXXXXXXXXXXXXXpDpD-3′ “SM70”5′-DXDXXXXXXXXXXXXXXXXXXXXDD-3′ “SM71” 5′-DpXDXXXXXXXXXXXXXXXXXXXXDD-3′“SM72” 5′-XXDXXXXXXXXXDXXXXXXXXXXDD-3′ “SM73”5′-XpXDXXXXXXXXXDXXXXXXXXXXDD-3′ “SM74” 5′-DXDXXXXXXXXXDXXXXXDXXXXDD-3′“SM75” 5′-DpXDXXXXXXXXXDXXXXXDXXXXDD-3′ “SM76”5′-XpXpXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM77”5′-XpXpXXXXXXXXXXXXXXXXXXXXXpDpD-3′ “SM78”5′-DpXpDXXXXXXXXXXXXXXXXXXXXDD-3′ “SM79”5′-XpXpDXXXXXXXXXDXXXXXXXXXXDD-3′ “SM80” 5′-DXDXXXDXXXXXDXXXXXDXXXXDD-3′“SM81” 5′-DpXDXXXDXXXXXDXXXXXDXXXXpDpD-3′ “SM82”5′ C3 spacer-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM83”5′ C3 spacer-XXDXXXXXXXXXDXXXXXXXXXXDD-3′ “SM84”5′ C3 spacer-XXXXXXXXXXXXXXXXXXXXXXXpDpD-3′ “SM85”5′-XXXXXXXXXXXXXXXXXXXXXXXpDpD-3′ “SM86”5′-XpXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM87”5′-XpXXXXXXXXXXXXXXXXXXXXXXpDpD-3′ “SM88”5′-DXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM89”5′-DpXXXXXXXXXXXXXXXXXXXXXXpDpD-3′ “SM90”5′-DXDXXXXXXXXXXXXXXXXXXXXDD-3′ “SM91” 5′-DpXDXXXXXXXXXXXXXXXXXXXXDD-3′“SM92” 5′-XXDXXXXXXXXXDXXXXXXXXXXDD-3′ “SM93”5′-XpXDXXXXXXXXXDXXXXXXXXXXDD-3′ “SM94” 5′-DXDXXXXXXXXXDXXXXXDXXXXDD-3′“SM95” 5′-DpXDXXXXXXXXXDXXXXXDXXXXDD-3′ “SM96”5′-XpXpXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM97”5′-XpXpXXXXXXXXXXXXXXXXXXXXXpDpD-3′ “SM98”5′-DpXpDXXXXXXXXXXXXXXXXXXXXDD-3′ “SM99”5′-XpXpDXXXXXXXXXDXXXXXXXXXXDD-3′ “SM100”5′-DXDXXXXXXXXXDXDXXXDDXXDDD-3′ “SM101”5′-DpXDXXXDXXXXXDXXXXXDXXXXpDpD-3′ “SM102”5′ C3 spacer-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM103”5′ C3 spacer-XXDXXXXXXXXXDXXXXXXXXXXDD-3′ “SM104”5′ C3 spacer-XXXXXXXXXXXXXXXXXXXXXXXpDpD-3′ “SM105”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM106” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′“SM107” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM108”5′-XFXXXXXXXXXXXXXXXFXXXXXDD-3′ “SM110” 5′-XXXFXFXXXXXXXFXXXXXXXXXDD-3′“SM111” 5′-XFXFXFXFXXXFXFXFXFXXXXXDD-3′ “SM112”5′-XpFXFXFXFXXXFXFXFXFXXXXXpDpD-3′ “SM113”5′-XFXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM114” 5′-XXXXFFXFXXXFXFXXXXXXXXXDD-3′“SM115” 5′-XFXFXXXXXXXXXXXXFXXXXXXDD-3′ “SM116”5′-XFXFFFXFXXXFXFXFFFXXXXXDD-3′ “SM117” 5′-XFXFXFXFXXXFXFXFXFXXXXXDD-3′“SM118” 5′-XpFXFXFXFXXXFXFXFXFXXXXXpDpD-3′ “SM119”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM250” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′“SM251” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM252”5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ “SM22” 5′-XXXXXXXXXXXXXXXXXXXXXXXXX-35′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′5′-XpXXXXXXXXXXXXXXXXXXXXXXDpD-3′ “SM120”5′-FpXFXFXFXFXFXFXFXFXFXFXXDpD-3′ “SM121”5′-XpXXXXXXXXXXXXXXXXXXXXXXDpD-3′ “SM122”5′-XpXXXXXXXXXXXXXXXXXXXXXXDpD-3′ “SM123”5′-FpXFXXXFXXXXXXXXXXXXXXXXpDpD-3′ “SM124”5′-FpXFXXXFXXXXXFXFXXXXXXXXpDpD-3′ “SM125”5′-FpXFXXXFXFFFXFXFXXXXXXXXpDpD-3′ “SM126”5′-FpXFXXXFXFFFXFXFXXXFFXXXpDpD-3′ “SM127”5′-FpXFXXXFXFFFXFXFXXXFFXXFpDpD-3′ “SM128”5′-FpXFXXXFXFFFXFXFXXXFFFFFpDpD-3′ “SM129”5′-FpXFXFXFXFXFXFXFXFXFXFXFpDpD-3′ “SM130”5′-XpXXXXXXXXXXXXXXXXXXXXXXXpX-3′ 5′-FpXFXFXFXFXFXFXFXFXFXFXXXpX-3′5′-XpXXXXXXXXXXXXXXXXXXXXXXXpX-3′ 5′-XpXXXXXXXXXXXXXXXXXXXXXXXpX-3′5′-FpXFXXXFXXXXXXXXXXXXXXXXpXpX-3′ 5′-FpXFXXXFXXXXXFXFXXXXXXXXpXpX-3′5′-FpXFXXXFXFFFXFXFXXXXXXXXpXpX-3′ 5′-FpXFXXXFXFFFXFXFXXXFFXXXpXpX-3′5′-FpXFXXXFXFFFXFXFXXXFFXXFpXpX-3′ 5′-FpXFXXXFXFFFXFXFXXXFFFFFpXpX-3′5′-FpXFXFXFXFXFXFXFXFXFXFXFpXpX-3′ 5′-XpXXXXXXXXXXXXXXXXXXXXXXpDpD-3′“SM133” 5′-XpXXXXXXXXXXXXXXXXXXXXXXpDpD-3′ “SM134”5′-XpXXXXXXXXXXXXXXXXXXXXXXpDpD-3′ “SM135”5′-XpXXXXXXXXXXXXXXXXXXXXXXpDpD-3′ “SM136”5′-XpXXXXXXXXXXXXXXXXXXXXXXpDpD-3′ “SM137”5′-XpXXXXXXXXXXXXXXXXXXXXXXpDpD-3′ “SM138”5′-XpXXXXXXXXXXXXXXXXXXXXXXpXpX-3′ 5′-XpXXXXXXXXXXXXXXXXXXXXXXpXpX-3′5′-XpXXXXXXXXXXXXXXXXXXXXXXpXpX-3′ 5′-XpXXXXXXXXXXXXXXXXXXXXXXpXpX-3′5′-XpXXXXXXXXXXXXXXXXXXXXXXpXpX-3′ 5′-XpXXXXXXXXXXXXXXXXXXXXXXpXpX-3′5′-XpXXXXXXXXXXXXXXXXXXXXXXDpD-3′ “SM140”5′-XpXXXXXXXXXXXXXXXXXXXXXXDpD-3′ “SM141”5′-XpXXXXXXXXXXXXXXXXXXXXXXDpD-3′ “SM142”5′-FpXFXFXFXFXFXFXFXFXFXXXFDpD-3′ “SM143”5′-FpXFXFXFXFXFXFXFXFXFFFFFDpD-3′ “SM144”5′-FpXFXFXFXFXFXFXFXFXFXXXXDpD-3′ “SM145”5′-FpXFXFXFXFXFXFXFXFXFXFXFDpD-3′ “SM146”5′-FXFXXXFXFFFXFXFXXXXXXXXDD-3′ “SM147” 5′-FXFXXXFXFFFXFXFXXXFFXXXDD-3′“SM148” 5′-FXFXXXFXFFFXFXFXXXFFXXFDD-3′ “SM149”5′-FXFXXXFXFFFXFXFXXXFFFFFDD-3′ “SM150”5′-FpXFXFXFXFFFXFXFXFXFFXXFDpD-3′ “SM151”5′-FpXFXFXFXFFXFXXFXFXFXXXXDpD-3′ “SM152”5′-FpXFXFXXFFFFFXXFXFXXFXXXDpD-3′ “SM153”5′-ab-XXFXXFFFXXFFXXXFFFFXpXXXDD-3′ “SM154” (ab = abasic for F7 stabilization at 5′ end)5′-XpXXXXXXXXXXXXXXXXXXXXXXXpX-3′ “SM155”5′-XpXXXXXXXXXXXXXXXXXXXXXXXpX-3′ “SM156”5′-FpXFXXXFFFFFFFXXXFXXFXXFXpX-3′ “SM157”5′-XpXFXFXXFFFFXFXFXFXXFXXXXpX-3′ “SM158”5′-FpXFXXXFXFFXFXXFXXXFXXXXXpX-3′ “SM159”5′-FpXFXFXFXFFFXFXFXFXFXXXXXX-3′ “SM160”5′-XpXXXXXXXXXXXXXXXXXXXXXXXpX-3′ 5′-XpXXXXXXXXXXXXXXXXXXXXXXXpX-3′5′-XpXXXXXXXXXXXXXXXXXXXXXXXpX-3′ 5′-FpXFXFXFXFXFXFXFXFXFXXXFXpX-3′5′-FpXFXFXFXFXFXFXFXFXFFFFFXpX-3′ 5′-FpXFXFXFXFXFXFXFXFXFXXXXXpX-3′5′-FpXFXFXFXFXFXFXFXFXFXFXFXpX-3′ 5′-FXFXXXFXFFFXFXFXXXXXXXXXX-3′5′-FXFXXXFXFFFXFXFXXXFFXXXXX-3′ 5′-FXFXXXFXFFFXFXFXXXFFXXFXX-3′5′-FXFXXXFXFFFXFXFXXXFFFFFXX-3′ 5′-FpXFXFXFXFFFXFXFXFXFFXXFXpX-3′5′-FpXFXFXFXFFXFXXFXFXFXXXXXpX-3′ 5′-FpXFXFXXFFFFFXXFXFXXFXXXXpX-3′5′-ab-XXFXXFFFXXFFXXXFFFFXpXXXXX-3′(ab = abasic for F7 stabilization at 5′ end)5′-XpXXXXXXXXXXXXXXXXXXXXXXXpX-3′ 5′-XpXXXXXXXXXXXXXXXXXXXXXXXpX-3′5′-FpXFXXXFFFFFFFXXXFXXFXXFXpX-3′ 5′-XpXFXFXXFFFFXFXFXFXXFXXXXpX-3′5′-FpXFXXXFXFFXFXXFXXXFXXXXXpX-3′ 5′-FpXFXFXFXFFFXFXFXFXFXXXXXX-3′5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM253” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′“SM255” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM256”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM257” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′“SM258” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM259”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM260” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′“SM261” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM262”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM263” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′“SM264” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM265”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM266” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′“SM267” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM268”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM269” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′“SM270” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM271”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM275” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′“SM276” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM277”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM278” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′“SM279” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM280”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM281” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′“SM282” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM283”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM284” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′“SM285” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM286”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM287” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′“SM288” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM289”5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM300”5′-XpXXXXXXXXXXXXXXXXXXXXXXDpD-3′ “SM301”5′-XpXXXXXXXXXXXXXXXXXXXXXXDpD-3′ “SM302”5′-XpXXXXXXXXXXXXXXXXXXXXXXDpD-3′ “SM303”5′-XpXXXXXXXXXXXXXXXXXXXXXXDpD-3′ “SM304”5′-XpXXXXXXXXXXXXXXXXXXXXXXDpD-3′ “SM305”5′-XpXXXXXXXXXXXXXXXXXXXXXXDpD-3′ “SM306”5′-XpXXXXXXXXXXXXXXXXXXXXXXDpD-3′ “SM307”5′-XpXXXXXXXXXXXXXXXXXXXXXXDpD-3′ “SM308”5′-XpXXXXXXXXXXXXXXXXXXXXXXDpD-3′ “SM309”5′-XpXXXXXXXXXXXXXXXXXXXXXXDpD-3′ “SM310”5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 5′-XpXXXXXXXXXXXXXXXXXXXXXXXpX-3′5′-XpXXXXXXXXXXXXXXXXXXXXXXXpX-3′ 5′-XpXXXXXXXXXXXXXXXXXXXXXXXpX-3′5′-XpXXXXXXXXXXXXXXXXXXXXXXXpX-3′ 5′-XpXXXXXXXXXXXXXXXXXXXXXXXpX-3′5′-XpXXXXXXXXXXXXXXXXXXXXXXXpX-3′ 5′-XpXXXXXXXXXXXXXXXXXXXXXXXpX-3′5′-XpXXXXXXXXXXXXXXXXXXXXXXXpX-3′ 5′-XpXXXXXXXXXXXXXXXXXXXXXXXpX-3′5′-XpXXXXXXXXXXXXXXXXXXXXXXXpX-3′where “X”=RNA, “X”=2′-O-methyl RNA, “D”=DNA, “F”=2′-Fluoro NA and“p”=Phosphorothioate linkage.

The above modification patterns can also be incorporated into, e.g., theextended DsiRNA structures and mismatch and/or frayed DsiRNA structuresdescribed below.

In another embodiment, the DsiRNA comprises strands having equal lengthspossessing 1-3 mismatched residues that serve to orient Dicer cleavage(specifically, one or more of positions 1, 2 or 3 on the first strand ofthe DsiRNA, when numbering from the 3′-terminal residue, are mismatchedwith corresponding residues of the 5′-terminal region on the secondstrand when first and second strands are annealed to one another). Anexemplary 27 mer DsiRNA agent with two terminal mismatched residues isshown:

5′-XXXXXXXXXXXXXXXXXXXXXXXX

3′-XXXXXXXXXXXXXXXXXXXXXXXX

wherein “X”=RNA, “M”=Nucleic acid residues (RNA, DNA or non-natural ormodified nucleic acids) that do not base pair (hydrogen bond) withcorresponding “M” residues of otherwise complementary strand whenstrands are annealed. Any of the residues of such agents can optionallybe 2′-O-methyl RNA monomers—alternating positioning of 2′-O-methyl RNAmonomers that commences from the 3′-terminal residue of the bottom(second) strand, as shown for above asymmetric agents, can also be usedin the above “blunt/fray” DsiRNA agent. In one embodiment, the topstrand is the sense strand, and the bottom strand is the antisensestrand. Alternatively, the bottom strand is the sense strand and the topstrand is the antisense strand.

In certain additional embodiments, the present invention providescompositions for RNA interference (RNAi) that possess one or more basepaired deoxyribonucleotides within a region of a double strandedribonucleic acid (dsRNA) that is positioned 3′ of a projected sensestrand Dicer cleavage site and correspondingly 5′ of a projectedantisense strand Dicer cleavage site. The compositions of the inventioncomprise a dsRNA which is a precursor molecule, i.e., the dsRNA of thepresent invention is processed in vivo to produce an active smallinterfering nucleic acid (siRNA). The dsRNA is processed by Dicer to anactive siRNA which is incorporated into RISC.

In certain embodiments, the DsiRNA agents of the invention can have thefollowing exemplary structures (noting that any of the followingexemplary structures can be combined, e.g., with the bottom strandmodification patterns of the above-described structures—in one specificexample, the bottom strand modification pattern shown in any of theabove structures is applied to the 27 most 3′ residues of the bottomstrand of any of the following structures; in another specific example,the bottom strand modification pattern shown in any of the abovestructures upon the 23 most 3′ residues of the bottom strand is appliedto the 23 most 3′ residues of the bottom strand of any of the followingstructures):

In one such embodiment, the DsiRNA comprises the following (an exemplary“right-extended”, “DNA extended” DsiRNA):

5′-XXXXXXXXXXXXXXXXXXXXXXXX_(N*)D_(N)DD-3′3′-YXXXXXXXXXXXXXXXXXXXXXXXX_(N*)D_(N)XX-5′wherein “X”=RNA, “Y” is an optional overhang domain comprised of 0-10RNA monomers that are optionally 2-O-methyl RNA monomers—in certainembodiments, “Y” is an overhang domain comprised of 1-4 RNA monomersthat are optionally 2-O-methyl RNA monomers, “D”=DNA, and “N”=1 to 50 ormore, but is optionally 1-8 or 1-10. “N*”=0 to 15 or more, but isoptionally 0, 1, 2, 3, 4, 5 or 6. In one embodiment, the top strand isthe sense strand, and the bottom strand is the antisense strand.Alternatively, the bottom strand is the sense strand and the top strandis the antisense strand.

In a related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXX_(N*)D_(N)DD-3′3′-YXXXXXXXXXXXXXXXXXXXXXXXX_(N*)D_(N)DD-5′wherein “X”=RNA, “Y” is an optional overhang domain comprised of 0-10RNA monomers that are optionally 2-O-methyl RNA monomers—in certainembodiments, “Y” is an overhang domain comprised of 1-4 RNA monomersthat are optionally 2′-O-methyl RNA monomers, “D”=DNA, and “N”=1 to 50or more, but is optionally 1-8 or 1-10. “N*”=0 to 15 or more, but isoptionally 0, 1, 2, 3, 4, 5 or 6. In one embodiment, the top strand isthe sense strand, and the bottom strand is the antisense strand.Alternatively, the bottom strand is the sense strand and the top strandis the antisense strand.

In an additional embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXX_(N*)D_(N)DD-3′3′-YXXXXXXXXXXXXXXXXXXXXXXXX_(N*)D_(N)ZZ-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an optional overhang domaincomprised of 0-10 RNA monomers that are optionally 2′-O-methyl RNAmonomers—in certain embodiments, “Y” is an overhang domain comprised of1-4 RNA monomers that are optionally 2′-O-methyl RNA monomers, “D”=DNA,“Z”=DNA or RNA, and “N”=1 to 50 or more, but is optionally 1-8 or 1-10.“N*”=0 to 15 or more, but is optionally 0, 1, 2, 3, 4, 5 or 6. In oneembodiment, the top strand is the sense strand, and the bottom strand isthe antisense strand. Alternatively, the bottom strand is the sensestrand and the top strand is the antisense strand, with 2′-O-methyl RNAmonomers located at alternating residues along the top strand, ratherthan the bottom strand presently depicted in the above schematic.

In another such embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXX_(N*)D_(N)DD-3′3′-YXXXXXXXXXXXXXXXXXXXXXXXX_(N*)D_(N)ZZ-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an optional overhang domaincomprised of 0-10 RNA monomers that are optionally 2′-O-methyl RNAmonomers—in certain embodiments, “Y” is an overhang domain comprised of1-4 RNA monomers that are optionally 2′-O-methyl RNA monomers, “D”=DNA,“Z”=DNA or RNA, and “N”=1 to 50 or more, but is optionally 1-8 or 1-10.“N*”=0 to 15 or more, but is optionally 0, 1, 2, 3, 4, 5 or 6. In oneembodiment, the top strand is the sense strand, and the bottom strand isthe antisense strand. Alternatively, the bottom strand is the sensestrand and the top strand is the antisense strand, with 2′-O-methyl RNAmonomers located at alternating residues along the top strand, ratherthan the bottom strand presently depicted in the above schematic.

In another such embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXX_(N*)D_(N)DD-3′3′-YXXXXXXXXXXXXXXXXXXXXXXXX_(N*)D_(N)ZZ-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an optional overhang domaincomprised of 0-10 RNA monomers that are optionally 2′-O-methyl RNAmonomers—in certain embodiments, “Y” is an overhang domain comprised of1-4 RNA monomers that are optionally 2′-O-methyl RNA monomers, “D”=DNA,“Z”=DNA or RNA, and “N”=1 to 50 or more, but is optionally 1-8 or 1-10.“N*”=0 to 15 or more, but is optionally 0, 1, 2, 3, 4, 5 or 6. In oneembodiment, the top strand is the sense strand, and the bottom strand isthe antisense strand. Alternatively, the bottom strand is the sensestrand and the top strand is the antisense strand, with 2′-O-methyl RNAmonomers located at alternating residues along the top strand, ratherthan the bottom strand presently depicted in the above schematic.

In another embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXX_(N*)[X1/D1]_(N)DD-3′3′-YXXXXXXXXXXXXXXXXXXXXXXXX_(N*)[X2/D2]_(N)ZZ-5′wherein “X”=RNA, “Y” is an optional overhang domain comprised of 0-10RNA monomers that are optionally 2′-O-methyl RNA monomers—in certainembodiments, “Y” is an overhang domain comprised of 1-4 RNA monomersthat are optionally 2′-O-methyl RNA monomers, “D”=DNA, “Z”=DNA or RNA,and “N”=1 to 50 or more, but is optionally 1-8 or 1-10, where at leastone D1_(N) is present in the top strand and is base paired with acorresponding D2_(N) in the bottom strand. Optionally, D1_(N) andD1_(N+1) are base paired with corresponding D2_(N) and D2_(N+1); D1_(N),D1_(N+1) and D1_(N+2) are base paired with corresponding D2_(N),D1_(N+1) and D1_(N+2), etc. “N*”=0 to 15 or more, but is optionally 0,1, 2, 3, 4, 5 or 6. In one embodiment, the top strand is the sensestrand, and the bottom strand is the antisense strand. Alternatively,the bottom strand is the sense strand and the top strand is theantisense strand, with 2′-O-methyl RNA monomers located at alternatingresidues along the top strand, rather than the bottom strand presentlydepicted in the above schematic.

In the structures depicted herein, the 5′ end of either the sense strandor antisense strand can optionally comprise a phosphate group.

In another embodiment, a DNA:DNA-extended DsiRNA comprises strandshaving equal lengths possessing 1-3 mismatched residues that serve toorient Dicer cleavage (specifically, one or more of positions 1, 2 or 3on the first strand of the DsiRNA, when numbering from the 3′-terminalresidue, are mismatched with corresponding residues of the 5′-terminalregion on the second strand when first and second strands are annealedto one another). An exemplary DNA:DNA-extended DsiRNA agent with twoterminal mismatched residues is shown:

5′-D_(N)XXXXXXXXXXXXXXXXXXXXXXXXX

3′-D_(N)XXXXXXXXXXXXXXXXXXXXXXXXX

wherein “X”=RNA, “M”=Nucleic acid residues (RNA, DNA or non-natural ormodified nucleic acids) that do not base pair (hydrogen bond) withcorresponding “M” residues of otherwise complementary strand whenstrands are annealed, “D”=DNA and “N”=1 to 50 or more, but is optionally1-15 or, optionally, 1-8. “N*”=0 to 15 or more, but is optionally 0, 1,2, 3, 4, 5 or 6. Any of the residues of such agents can optionally be2′-O-methyl RNA monomers—alternating positioning of 2′-O-methyl RNAmonomers that commences from the 3′-terminal residue of the bottom(second) strand, as shown for above asymmetric agents, can also be usedin the above “blunt/fray” DsiRNA agent. In one embodiment, the topstrand (first strand) is the sense strand, and the bottom strand (secondstrand) is the antisense strand. Alternatively, the bottom strand is thesense strand and the top strand is the antisense strand. Modificationand DNA:DNA extension patterns paralleling those shown above forasymmetric/overhang agents can also be incorporated into such“blunt/frayed” agents.

In one embodiment, a length-extended DsiRNA agent is provided thatcomprises deoxyribonucleotides positioned at sites modeled to functionvia specific direction of Dicer cleavage, yet which does not require thepresence of a base-paired deoxyribonucleotide in the dsRNA structure. Anexemplary structure for such a molecule is shown:

5′-XXXXXXXXXXXXXXXXXXXDDXX-3′ 3′-YXXXXXXXXXXXXXXXXXDDXXXX-5′wherein “X”=RNA, “Y” is an optional overhang domain comprised of 0-10RNA monomers that are optionally 2′-O-methyl RNA monomers—in certainembodiments, “Y” is an overhang domain comprised of 1-4 RNA monomersthat are optionally 2′-O-methyl RNA monomers, and “D”=DNA. In oneembodiment, the top strand is the sense strand, and the bottom strand isthe antisense strand. Alternatively, the bottom strand is the sensestrand and the top strand is the antisense strand. The above structureis modeled to force Dicer to cleave a minimum of a 21 mer duplex as itsprimary post-processing form. In embodiments where the bottom strand ofthe above structure is the antisense strand, the positioning of twodeoxyribonucleotide residues at the ultimate and penultimate residues ofthe 5′ end of the antisense strand will help reduce off-target effects(as prior studies have shown a 2′-O-methyl modification of at least thepenultimate position from the 5′ terminus of the antisense strand toreduce off-target effects; see, e.g., US 2007/0223427).

In one embodiment, the DsiRNA comprises the following (an exemplary“left-extended”, “DNA extended” DsiRNA):

5′-D_(N)XXXXXXXXXXXXXXXXXXXXXXXX_(N*)Y-3′3′-D_(N)XXXXXXXXXXXXXXXXXXXXXXXX_(N*)-5′wherein “X”=RNA, “Y” is an optional overhang domain comprised of 0-10RNA monomers that are optionally 2′-O-methyl RNA monomers—in certainembodiments, “Y” is an overhang domain comprised of 1-4 RNA monomersthat are optionally 2′-O-methyl RNA monomers, “D”=DNA, and “N”=1 to 50or more, but is optionally 1-8 or 1-10. “N*”=0 to 15 or more, but isoptionally 0, 1, 2, 3, 4, 5 or 6. In one embodiment, the top strand isthe sense strand, and the bottom strand is the antisense strand.Alternatively, the bottom strand is the sense strand and the top strandis the antisense strand.

In a related embodiment, the DsiRNA comprises:

5′-D_(N)XXXXXXXXXXXXXXXXXXXXXXXX_(N*)DD-3′3′-D_(N)XXXXXXXXXXXXXXXXXXXXXXXX_(N*)XX-5′wherein “X”=RNA, optionally a 2′-O-methyl RNA monomers “D”=DNA, “N”=1 to50 or more, but is optionally 1-8 or 1-10. “N*”=0 to 15 or more, but isoptionally 0, 1, 2, 3, 4, 5 or 6. In one embodiment, the top strand isthe sense strand, and the bottom strand is the antisense strand.Alternatively, the bottom strand is the sense strand and the top strandis the antisense strand.

In an additional embodiment, the DsiRNA comprises:

5′-D_(N)XXXXXXXXXXXXXXXXXXXXXXXX_(N*)DD-3′ 3′-D_(N)XXXXXXXXXXXXXXXXXXXXXXXX_(N*)ZZ-5′wherein “X”=RNA, optionally a 2′-O-methyl RNA monomers “D”=DNA, “N”=1 to50 or more, but is optionally 1-8 or 1-10. “N*”=0 to 15 or more, but isoptionally 0, 1, 2, 3, 4, 5 or 6. “Z”=DNA or RNA. In one embodiment, thetop strand is the sense strand, and the bottom strand is the antisensestrand. Alternatively, the bottom strand is the sense strand and the topstrand is the antisense strand, with 2′-O-methyl RNA monomers located atalternating residues along the top strand, rather than the bottom strandpresently depicted in the above schematic.

In another such embodiment, the DsiRNA comprises:

5′-D_(N)XXXXXXXXXXXXXXXXXXXXXXXX_(N*)DD-3′ 3′-D_(N)XXXXXXXXXXXXXXXXXXXXXXXX_(N*)ZZ-5′wherein “X”=RNA, optionally a 2′-O-methyl RNA monomers “D”=DNA, “N”=1 to50 or more, but is optionally 1-8 or 1-10. “N*”=0 to 15 or more, but isoptionally 0, 1, 2, 3, 4, 5 or 6. “Z”=DNA or RNA. In one embodiment, thetop strand is the sense strand, and the bottom strand is the antisensestrand. Alternatively, the bottom strand is the sense strand and the topstrand is the antisense strand, with 2′-O-methyl RNA monomers located atalternating residues along the top strand, rather than the bottom strandpresently depicted in the above schematic.

In another such embodiment, the DsiRNA comprises:

5′-D_(N)ZZXXXXXXXXXXXXXXXXXXXXXXXX_(N*)DD-3′ 3′-D_(N)XXXXXXXXXXXXXXXXXXXXXXXXXX_(N*)ZZ-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “D”=DNA, “Z”=DNA or RNA, and “N”=1to 50 or more, but is optionally 1-8 or 1-10. “N*”=0 to 15 or more, butis optionally 0, 1, 2, 3, 4, 5 or 6. In one embodiment, the top strandis the sense strand, and the bottom strand is the antisense strand.Alternatively, the bottom strand is the sense strand and the top strandis the antisense strand, with 2′-O-methyl RNA monomers located atalternating residues along the top strand, rather than the bottom strandpresently depicted in the above schematic.

In another such embodiment, the DsiRNA comprises:

5′-D_(N)ZZXXXXXXXXXXXXXXXXXXXXXXXX_(N*)Y-3′ 3′-D_(N)XXXXXXXXXXXXXXXXXXXXXXXXXX_(N*)-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “D”=DNA, “Z”=DNA or RNA, and “N”=1to 50 or more, but is optionally 1-8 or 1-10. “N*”=0 to 15 or more, butis optionally 0, 1, 2, 3, 4, 5 or 6. “Y” is an optional overhang domaincomprised of 0-10 RNA monomers that are optionally 2′-O-methyl RNAmonomers—in certain embodiments, “Y” is an overhang domain comprised of1-4 RNA monomers that are optionally 2′-O-methyl RNA monomers. In oneembodiment, the top strand is the sense strand, and the bottom strand isthe antisense strand. Alternatively, the bottom strand is the sensestrand and the top strand is the antisense strand, with 2′-O-methyl RNAmonomers located at alternating residues along the top strand, ratherthan the bottom strand presently depicted in the above schematic.

In another embodiment, the DsiRNA comprises:

5′-[X1/D1]_(N)XXXXXXXXXXXXXXXXXXXXXXXX_(N*)DD-3′3′-[X2/D2]_(N)XXXXXXXXXXXXXXXXXXXXXXXX_(N*)ZZ-5′wherein “X”=RNA, “D”=DNA, “Z”=DNA or RNA, and “N”=1 to 50 or more, butis optionally 1-8 or 1-10, where at least one DIN is present in the topstrand and is base paired with a corresponding D2_(N) in the bottomstrand. Optionally, DIN and D1_(N+1) are base paired with correspondingD2_(N) and D2_(N+1); D1_(N), D1_(N+1) and D1_(N+2) are base paired withcorresponding D2_(N), D1_(N+1) and D1_(N+2), etc. “N*”=0 to 15 or more,but is optionally 0, 1, 2, 3, 4, 5 or 6. In one embodiment, the topstrand is the sense strand, and the bottom strand is the antisensestrand. Alternatively, the bottom strand is the sense strand and the topstrand is the antisense strand, with 2′-O-methyl RNA monomers located atalternating residues along the top strand, rather than the bottom strandpresently depicted in the above schematic.

In a related embodiment, the DsiRNA comprises:

5′-[X1/D1]_(N)XXXXXXXXXXXXXXXXXXXXXXXX_(N*)Y-3′3′-[X2/D2]_(N)XXXXXXXXXXXXXXXXXXXXXXXX_(N*)-5′wherein “X”=RNA, “D”=DNA, “Y” is an optional overhang domain comprisedof 0-10 RNA monomers that are optionally 2′-O-methyl RNA monomers—incertain embodiments, “Y” is an overhang domain comprised of 1-4 RNAmonomers that are optionally 2′-O-methyl RNA monomers, and “N”=1 to 50or more, but is optionally 1-8 or 1-10, where at least one DIN ispresent in the top strand and is base paired with a corresponding D2_(N)in the bottom strand. Optionally, DIN and D1_(N+1) are base paired withcorresponding D2_(N) and D2_(N+1); D1_(N), D1_(N+1) and D1_(N+2) arebase paired with corresponding D2_(N), D1_(N+1) and D1_(N+2), etc.“N*”=0 to 15 or more, but is optionally 0, 1, 2, 3, 4, 5 or 6. In oneembodiment, the top strand is the sense strand, and the bottom strand isthe antisense strand. Alternatively, the bottom strand is the sensestrand and the top strand is the antisense strand, with 2′-O-methyl RNAmonomers located at alternating residues along the top strand, ratherthan the bottom strand presently depicted in the above schematic.

In another embodiment, the DNA:DNA-extended DsiRNA comprises strandshaving equal lengths possessing 1-3 mismatched residues that serve toorient Dicer cleavage (specifically, one or more of positions 1, 2 or 3on the first strand of the DsiRNA, when numbering from the 3′-terminalresidue, are mismatched with corresponding residues of the 5′-terminalregion on the second strand when first and second strands are annealedto one another). An exemplary DNA:DNA-extended DsiRNA agent with twoterminal mismatched residues is shown:

5′-D_(N)XXXXXXXXXXXXXXXXXXXXXXXXX

3′-D_(N)XXXXXXXXXXXXXXXXXXXXXXXXX

wherein “X”=RNA, “M”=Nucleic acid residues (RNA, DNA or non-natural ormodified nucleic acids) that do not base pair (hydrogen bond) withcorresponding “M” residues of otherwise complementary strand whenstrands are annealed, “D”=DNA and “N”=1 to 50 or more, but is optionally1-8 or 1-10. “N*”=0 to 15 or more, but is optionally 0, 1, 2, 3, 4, 5 or6. Any of the residues of such agents can optionally be 2′-O-methyl RNAmonomers—alternating positioning of 2′-O-methyl RNA monomers thatcommences from the 3′-terminal residue of the bottom (second) strand, asshown for above asymmetric agents, can also be used in the above“blunt/fray” DsiRNA agent. In one embodiment, the top strand (firststrand) is the sense strand, and the bottom strand (second strand) isthe antisense strand. Alternatively, the bottom strand is the sensestrand and the top strand is the antisense strand. Modification andDNA:DNA extension patterns paralleling those shown above forasymmetric/overhang agents can also be incorporated into such“blunt/frayed” agents.

In another embodiment, a length-extended DsiRNA agent is provided thatcomprises deoxyribonucleotides positioned at sites modeled to functionvia specific direction of Dicer cleavage, yet which does not require thepresence of a base-paired deoxyribonucleotide in the dsRNA structure.Exemplary structures for such a molecule are shown:

5′-XXDDXXXXXXXXXXXXXXXXXXXX_(N*)Y-3′ 3′-DDXXXXXXXXXXXXXXXXXXXXXX_(N*)-5′or 5′-XDXDXXXXXXXXXXXXXXXXXXXX_(N*)Y-3′3′-DXDXXXXXXXXXXXXXXXXXXXXX_(N*)-5′wherein “X”=RNA, “Y” is an optional overhang domain comprised of 0-10RNA monomers that are optionally 2′-O-methyl RNA monomers—in certainembodiments, “Y” is an overhang domain comprised of 1-4 RNA monomersthat are optionally 2′-O-methyl RNA monomers, and “D”=DNA. “N*”=0 to 15or more, but is optionally 0, 1, 2, 3, 4, 5 or 6. In one embodiment, thetop strand is the sense strand, and the bottom strand is the antisensestrand. Alternatively, the bottom strand is the sense strand and the topstrand is the antisense strand.

In any of the above embodiments where the bottom strand of the abovestructure is the antisense strand, the positioning of twodeoxyribonucleotide residues at the ultimate and penultimate residues ofthe 5′ end of the antisense strand will help reduce off-target effects(as prior studies have shown a 2′-O-methyl modification of at least thepenultimate position from the 5′ terminus of the antisense strand toreduce off-target effects; see, e.g., US 2007/0223427).

In certain embodiments, the “D” residues of the above structures includeat least one PS-DNA or PS-RNA. Optionally, the “D” residues of the abovestructures include at least one modified nucleotide that inhibits Dicercleavage.

While the above-described “DNA-extended” DsiRNA agents can becategorized as either “left extended” or “right extended”, DsiRNA agentscomprising both left- and right-extended DNA-containing sequences withina single agent (e.g., both flanks surrounding a core dsRNA structure aredsDNA extensions) can also be generated and used in similar manner tothose described herein for “right-extended” and “left-extended” agents.

In some embodiments, the DsiRNA of the instant invention furthercomprises a linking moiety or domain that joins the sense and antisensestrands of a DNA:DNA-extended DsiRNA agent. Optionally, such a linkingmoiety domain joins the 3′ end of the sense strand and the 5′ end of theantisense strand. The linking moiety may be a chemical (non-nucleotide)linker, such as an oligomethylenediol linker, oligoethylene glycollinker, or other art-recognized linker moiety. Alternatively, the linkercan be a nucleotide linker, optionally including an extended loop and/ortetraloop.

In one embodiment, the DsiRNA agent has an asymmetric structure, withthe sense strand having a 25-base pair length, and the antisense strandhaving a 27-base pair length with a 1-4 base 3′-overhang (e.g., a onebase 3′-overhang, a two base 3′-overhang, a three base 3′-overhang or afour base 3′-overhang). In another embodiment, this DsiRNA agent has anasymmetric structure further containing 2 deoxynucleotides at the 3′ endof the sense strand.

In another embodiment, the DsiRNA agent has an asymmetric structure,with the antisense strand having a 25-base pair length, and the sensestrand having a 27-base pair length with a 1-4 base 3′-overhang (e.g., aone base 3′-overhang, a two base 3′-overhang, a three base 3′-overhangor a four base 3′-overhang). In another embodiment, this DsiRNA agenthas an asymmetric structure further containing 2 deoxyribonucleotides atthe 3′ end of the antisense strand.

Exemplary transthyretin targeting DsiRNA agents of the invention, andtheir associated transthyretin target sequences, include the following,presented in the below series of tables:

Table Number:

(2) Selected Human Anti-transthyretin DsiRNA Agents (Asymmetrics);

(3) Selected Human Anti-transthyretin DsiRNAs, Unmodified Duplexes(Asymmetrics);

(4) DsiRNA Target Sequences (21 mers) in Transthyretin mRNA;

(5) Selected Human Anti-Transthyretin “Blunt/Blunt” DsiRNAs; and

(6) DsiRNA Component 19 Nucleotide Target Sequences in TransthyretinmRNA

TABLE 2 Selected Human Anti-transthyretin DsiRNA Agents (Asymmetrics)5′-UGACUAAGUCAAUAAUCAGAAUCag-3′ (SEQ ID NO: 1)3′-CAACUGAUUCAGUUAUUAGUCUUAGUC-5′ (SEQ ID NO: 385) TTR-27 Target:5′-GTTGACTAAGTCAATAATCAGAATCAG-3′ (SEQ ID NO: 769)5′-GACUAAGUCAAUAAUCAGAAUCAgc-3′ (SEQ ID NO: 2)3′-AACUGAUUCAGUUAUUAGUCUUAGUCG-5′ (SEQ ID NO: 386) TTR-28 Target:5′-TTGACTAAGTCAATAATCAGAATCAGC-3′ (SEQ ID NO: 770)5′-ACUAAGUCAAUAAUCAGAAUCAGca-3′ (SEQ ID NO: 3)3′-ACUGAUUCAGUUAUUAGUCUUAGUCGU-5′ (SEQ ID NO: 387) TTR-29 Target:5′-TGACTAAGTCAATAATCAGAATCAGCA-3′ (SEQ ID NO: 771)5′-CUAAGUCAAUAAUCAGAAUCAGCag-3′ (SEQ ID NO: 4)3′-CUGAUUCAGUUAUUAGUCUUAGUCGUC-5′ (SEQ ID NO: 388) TTR-30 Target:5′-GACTAAGTCAATAATCAGAATCAGCAG-3′ (SEQ ID NO: 772)5′-UAAGUCAAUAAUCAGAAUCAGCAgg-3′ (SEQ ID NO: 5)3′-UGAUUCAGUUAUUAGUCUUAGUCGUCC-5′ (SEQ ID NO: 389) TTR-31 Target:5′-ACTAAGTCAATAATCAGAATCAGCAGG-3′ (SEQ ID NO: 773)5′-AAGUCAAUAAUCAGAAUCAGCAGgt-3′ (SEQ ID NO: 6)3′-GAUUCAGUUAUUAGUCUUAGUCGUCCA-5′ (SEQ ID NO: 390) TTR-32 Target:5′-CTAAGTCAATAATCAGAATCAGCAGGT-3′ (SEQ ID NO: 774)5′-AGUCAAUAAUCAGAAUCAGCAGGtt-3′ (SEQ ID NO: 7)3′-AUUCAGUUAUUAGUCUUAGUCGUCCAA-5′ (SEQ ID NO: 391) TTR-33 Target:5′-TAAGTCAATAATCAGAATCAGCAGGTT-3′ (SEQ ID NO: 775)5′-GUCAAUAAUCAGAAUCAGCAGGUtt-3′ (SEQ ID NO: 8)3′-UUCAGUUAUUAGUCUUAGUCGUCCAAA-5′ (SEQ ID NO: 392) TTR-34 Target:5′-AAGTCAATAATCAGAATCAGCAGGTTT-3′ (SEQ ID NO: 776)5′-UCAAUAAUCAGAAUCAGCAGGUUtg-3′ (SEQ ID NO: 9)3′-UCAGUUAUUAGUCUUAGUCGUCCAAAC-5′ (SEQ ID NO: 393) TTR-35 Target:5′-AGTCAATAATCAGAATCAGCAGGTTTG-3′ (SEQ ID NO: 777)5′-CAAUAAUCAGAAUCAGCAGGUUUgc-3′ (SEQ ID NO: 10)3′-CAGUUAUUAGUCUUAGUCGUCCAAACG-5′ (SEQ ID NO: 394) TTR-36 Target:5′-GTCAATAATCAGAATCAGCAGGTTTGC-3′ (SEQ ID NO: 778)5′-AAUAAUCAGAAUCAGCAGGUUUGca-3′ (SEQ ID NO: 11)3′-AGUUAUUAGUCUUAGUCGUCCAAACGU-5′ (SEQ ID NO: 395) TTR-37 Target:5′-TCAATAATCAGAATCAGCAGGTTTGCA-3′ (SEQ ID NO: 779)5′-AUAAUCAGAAUCAGCAGGUUUGCag-3′ (SEQ ID NO: 12)3′-GUUAUUAGUCUUAGUCGUCCAAACGUC-5′ (SEQ ID NO: 396) TTR-38 Target:5′-CAATAATCAGAATCAGCAGGTTTGCAG-3′ (SEQ ID NO: 780)5′-UAAUCAGAAUCAGCAGGUUUGCAgt-3′ (SEQ ID NO: 13)3′-UUAUUAGUCUUAGUCGUCCAAACGUCA-5′ (SEQ ID NO: 397) TTR-39 Target:5′-AATAATCAGAATCAGCAGGTTTGCAGT-3′ (SEQ ID NO: 781)5′-AAUCAGAAUCAGCAGGUUUGCAGtc-3′ (SEQ ID NO: 14)3′-UAUUAGUCUUAGUCGUCCAAACGUCAG-5′ (SEQ ID NO: 398) TTR-40 Target:5′-ATAATCAGAATCAGCAGGTTTGCAGTC-3′ (SEQ ID NO: 782)5′-AUCAGAAUCAGCAGGUUUGCAGUca-3′ (SEQ ID NO: 15)3′-AUUAGUCUUAGUCGUCCAAACGUCAGU-5′ (SEQ ID NO: 399) TTR-41 Target:5′-TAATCAGAATCAGCAGGTTTGCAGTCA-3′ (SEQ ID NO: 783)5′-CAGAAUCAGCAGGUUUGCAGUCAga-3′ (SEQ ID NO: 16)3′-UAGUCUUAGUCGUCCAAACGUCAGUCU-5′ (SEQ ID NO: 400) TTR-43 Target:5′-ATCAGAATCAGCAGGTTTGCAGTCAGA-3′ (SEQ ID NO: 784)5′-AGAAUCAGCAGGUUUGCAGUCAGat-3′ (SEQ ID NO: 17)3′-AGUCUUAGUCGUCCAAACGUCAGUCUA-5′ (SEQ ID NO: 401) TTR-44 Target:5′-TCAGAATCAGCAGGTTTGCAGTCAGAT-3′ (SEQ ID NO: 785)5′-AAUCAGCAGGUUUGCAGUCAGAUtg-3′ (SEQ ID NO: 18)3′-UCUUAGUCGUCCAAACGUCAGUCUAAC-5′ (SEQ ID NO: 402) TTR-46 Target:5′-AGAATCAGCAGGTTTGCAGTCAGATTG-3′ (SEQ ID NO: 786)5′-AUCAGCAGGUUUGCAGUCAGAUUgg-3′ (SEQ ID NO: 19)3′-CUUAGUCGUCCAAACGUCAGUCUAACC-5′ (SEQ ID NO: 403) TTR-47 Target:5′-GAATCAGCAGGTTTGCAGTCAGATTGG-3′ (SEQ ID NO: 787)5′-GCAGUCAGAUUGGCAGGGAUAAGca-3′ (SEQ ID NO: 20)3′-AACGUCAGUCUAACCGUCCCUAUUCGU-5′ (SEQ ID NO: 404) TTR-59 Target:5′-TTGCAGTCAGATTGGCAGGGATAAGCA-3′ (SEQ ID NO: 788)5′-GCCUAGCUCAGGAGAAGUGAGUAta-3′ (SEQ ID NO: 21)3′-GUCGGAUCGAGUCCUCUUCACUCAUAU-5′ (SEQ ID NO: 405) TTR-84 Target:5′-CAGCCTAGCTCAGGAGAAGTGAGTATA-3′ (SEQ ID NO: 789)5′-UAGCUCAGGAGAAGUGAGUAUAAaa-3′ (SEQ ID NO: 22)3′-GGAUCGAGUCCUCUUCACUCAUAUUUU-5′ (SEQ ID NO: 406) TTR-87 Target:5′-CCTAGCTCAGGAGAAGTGAGTATAAAA-3′ (SEQ ID NO: 790)5′-AGCUCAGGAGAAGUGAGUAUAAAag-3′ (SEQ ID NO: 23)3′-GAUCGAGUCCUCUUCACUCAUAUUUUC-5′ (SEQ ID NO: 407) TTR-88 Target:5′-CTAGCTCAGGAGAAGTGAGTATAAAAG-3′ (SEQ ID NO: 791)5′-GCUCAGGAGAAGUGAGUAUAAAAgc-3′ (SEQ ID NO: 24)3′-AUCGAGUCCUCUUCACUCAUAUUUUCG-5′ (SEQ ID NO: 408) TTR-89 Target:5′-TAGCTCAGGAGAAGTGAGTATAAAAGC-3′ (SEQ ID NO: 792)5′-CUCAGGAGAAGUGAGUAUAAAAGcc-3′ (SEQ ID NO: 25)3′-UCGAGUCCUCUUCACUCAUAUUUUCGG-5′ (SEQ ID NO: 409) TTR-90 Target:5′-AGCTCAGGAGAAGTGAGTATAAAAGCC-3′ (SEQ ID NO: 793)5′-CAGGAGAAGUGAGUAUAAAAGCCcc-3′ (SEQ ID NO: 26)3′-GAGUCCUCUUCACUCAUAUUUUCGGGG-5′ (SEQ ID NO: 410) TTR-92 Target:5′-CTCAGGAGAAGTGAGTATAAAAGCCCC-3′ (SEQ ID NO: 794)5′-GCAGCCAUCACAGAAGUCCACUCat-3′ (SEQ ID NO: 27)3′-CUCGUCGGUAGUGUCUUCAGGUGAGUA-5′ (SEQ ID NO: 411) TTR-126 Target:5′-GAGCAGCCATCACAGAAGTCCACTCAT-3′ (SEQ ID NO: 795)5′-CAGCCAUCACAGAAGUCCACUCAtt-3′ (SEQ ID NO: 28)3′-UCGUCGGUAGUGUCUUCAGGUGAGUAA-5′ (SEQ ID NO: 412) TTR-127 Target:5′-AGCAGCCATCACAGAAGTCCACTCATT-3′ (SEQ ID NO: 796)5′-AGCCAUCACAGAAGUCCACUCAUtc-3′ (SEQ ID NO: 29)3′-CGUCGGUAGUGUCUUCAGGUGAGUAAG-5′ (SEQ ID NO: 413) TTR-128 Target:5′-GCAGCCATCACAGAAGTCCACTCATTC-3′ (SEQ ID NO: 797)5′-GCCAUCACAGAAGUCCACUCAUUct-3′ (SEQ ID NO: 30)3′-GUCGGUAGUGUCUUCAGGUGAGUAAGA-5′ (SEQ ID NO: 414) TTR-129 Target:5′-CAGCCATCACAGAAGTCCACTCATTCT-3′ (SEQ ID NO: 798)5′-CCAUCACAGAAGUCCACUCAUUCtt-3′ (SEQ ID NO: 31)3′-UCGGUAGUGUCUUCAGGUGAGUAAGAA-5′ (SEQ ID NO: 415) TTR-130 Target:5′-AGCCATCACAGAAGTCCACTCATTCTT-3′ (SEQ ID NO: 799)5′-CAUCACAGAAGUCCACUCAUUCUtg-3′ (SEQ ID NO: 32)3′-CGGUAGUGUCUUCAGGUGAGUAAGAAC-5′ (SEQ ID NO: 416) TTR-131 Target:5′-GCCATCACAGAAGTCCACTCATTCTTG-3′ (SEQ ID NO: 800)5′-AUCACAGAAGUCCACUCAUUCUUgg-3′ (SEQ ID NO: 33)3′-GGUAGUGUCUUCAGGUGAGUAAGAACC-5′ (SEQ ID NO: 417) TTR-132 Target:5′-CCATCACAGAAGTCCACTCATTCTTGG-3′ (SEQ ID NO: 801)5′-CACAGAAGUCCACUCAUUCUUGGca-3′ (SEQ ID NO: 34)3′-UAGUGUCUUCAGGUGAGUAAGAACCGU-5′ (SEQ ID NO: 418) TTR-134 Target:5′-ATCACAGAAGTCCACTCATTCTTGGCA-3′ (SEQ ID NO: 802)5′-ACAGAAGUCCACUCAUUCUUGGCag-3′ (SEQ ID NO: 35)3′-AGUGUCUUCAGGUGAGUAAGAACCGUC-5′ (SEQ ID NO: 419) TTR-135 Target:5′-TCACAGAAGTCCACTCATTCTTGGCAG-3′ (SEQ ID NO: 803)5′-UUCUUGGCAGGAUGGCUUCUCAUcg-3′ (SEQ ID NO: 36)3′-GUAAGAACCGUCCUACCGAAGAGUAGC-5′ (SEQ ID NO: 420) TTR-150 Target:5′-CATTCTTGGCAGGATGGCTTCTCATCG-3′ (SEQ ID NO: 804)5′-UCUUGGCAGGAUGGCUUCUCAUCgt-3′ (SEQ ID NO: 37)3′-UAAGAACCGUCCUACCGAAGAGUAGCA-5′ (SEQ ID NO: 421) TTR-151 Target:5′-ATTCTTGGCAGGATGGCTTCTCATCGT-3′ (SEQ ID NO: 805)5′-CUUGGCAGGAUGGCUUCUCAUCGtc-3′ (SEQ ID NO: 38)3′-AAGAACCGUCCUACCGAAGAGUAGCAG-5′ (SEQ ID NO: 422) TTR-152 Target:5′-TTCTTGGCAGGATGGCTTCTCATCGTC-3′ (SEQ ID NO: 806)5′-UUGGCAGGAUGGCUUCUCAUCGUct-3′ (SEQ ID NO: 39)3′-AGAACCGUCCUACCGAAGAGUAGCAGA-5′ (SEQ ID NO: 423) TTR-153 Target:5′-TCTTGGCAGGATGGCTTCTCATCGTCT-3′ (SEQ ID NO: 807)5′-UGGCAGGAUGGCUUCUCAUCGUCtg-3′ (SEQ ID NO: 40)3′-GAACCGUCCUACCGAAGAGUAGCAGAC-5′ (SEQ ID NO: 424) TTR-154 Target:5′-CTTGGCAGGATGGCTTCTCATCGTCTG-3′ (SEQ ID NO: 808)5′-GGCAGGAUGGCUUCUCAUCGUCUgc-3′ (SEQ ID NO: 41)3′-AACCGUCCUACCGAAGAGUAGCAGACG-5′ (SEQ ID NO: 425) TTR-155 Target:5′-TTGGCAGGATGGCTTCTCATCGTCTGC-3′ (SEQ ID NO: 809)5′-GCAGGAUGGCUUCUCAUCGUCUGct-3′ (SEQ ID NO: 42)3′-ACCGUCCUACCGAAGAGUAGCAGACGA-5′ (SEQ ID NO: 426) TTR-156 Target:5′-TGGCAGGATGGCTTCTCATCGTCTGCT-3′ (SEQ ID NO: 810)5′-CAGGAUGGCUUCUCAUCGUCUGCtc-3′ (SEQ ID NO: 43)3′-CCGUCCUACCGAAGAGUAGCAGACGAG-5′ (SEQ ID NO: 427) TTR-157 Target:5′-GGCAGGATGGCTTCTCATCGTCTGCTC-3′ (SEQ ID NO: 811)5′-AGGAUGGCUUCUCAUCGUCUGCUcc-3′ (SEQ ID NO: 44)3′-CGUCCUACCGAAGAGUAGCAGACGAGG-5′ (SEQ ID NO: 428) TTR-158 Target:5′-GCAGGATGGCTTCTCATCGTCTGCTCC-3′ (SEQ ID NO: 812)5′-GGAUGGCUUCUCAUCGUCUGCUCct-3′ (SEQ ID NO: 45)3′-GUCCUACCGAAGAGUAGCAGACGAGGA-5′ (SEQ ID NO: 429) TTR-159 Target:5′-CAGGATGGCTTCTCATCGTCTGCTCCT-3′ (SEQ ID NO: 813)5′-GAUGGCUUCUCAUCGUCUGCUCCtc-3′ (SEQ ID NO: 46)3′-UCCUACCGAAGAGUAGCAGACGAGGAG-5′ (SEQ ID NO: 430) TTR-160 Target:5′-AGGATGGCTTCTCATCGTCTGCTCCTC-3′ (SEQ ID NO: 814)5′-AUGGCUUCUCAUCGUCUGCUCCUcc-3′ (SEQ ID NO: 47)3′-CCUACCGAAGAGUAGCAGACGAGGAGG-5′ (SEQ ID NO: 431) TTR-161 Target:5′-GGATGGCTTCTCATCGTCTGCTCCTCC-3′ (SEQ ID NO: 815)5′-UGGCUUCUCAUCGUCUGCUCCUCct-3′ (SEQ ID NO: 48)3′-CUACCGAAGAGUAGCAGACGAGGAGGA-5′ (SEQ ID NO: 432) TTR-162 Target:5′-GATGGCTTCTCATCGTCTGCTCCTCCT-3′ (SEQ ID NO: 816)5′-GGCUUCUCAUCGUCUGCUCCUCCtc-3′ (SEQ ID NO: 49)3′-UACCGAAGAGUAGCAGACGAGGAGGAG-5′ (SEQ ID NO: 433) TTR-163 Target:5′-ATGGCTTCTCATCGTCTGCTCCTCCTC-3′ (SEQ ID NO: 817)5′-GCUUCUCAUCGUCUGCUCCUCCUct-3′ (SEQ ID NO: 50)3′-ACCGAAGAGUAGCAGACGAGGAGGAGA-5′ (SEQ ID NO: 434) TTR-164 Target:5′-TGGCTTCTCATCGTCTGCTCCTCCTCT-3′ (SEQ ID NO: 818)5′-CUUCUCAUCGUCUGCUCCUCCUCtg-3′ (SEQ ID NO: 51)3′-CCGAAGAGUAGCAGACGAGGAGGAGAC-5′ (SEQ ID NO: 435) TTR-165 Target:5′-GGCTTCTCATCGTCTGCTCCTCCTCTG-3′ (SEQ ID NO: 819)5′-UCUGCCUUGCUGGACUGGUAUUUgt-3′ (SEQ ID NO: 52)3′-GGAGACGGAACGACCUGACCAUAAACA-5′ (SEQ ID NO: 436) TTR-186 Target:5′-CCTCTGCCTTGCTGGACTGGTATTTGT-3′ (SEQ ID NO: 820)5′-CUGCCUUGCUGGACUGGUAUUUGtg-3′ (SEQ ID NO: 53)3′-GAGACGGAACGACCUGACCAUAAACAC-5′ (SEQ ID NO: 437) TTR-187 Target:5′-CTCTGCCTTGCTGGACTGGTATTTGTG-3′ (SEQ ID NO: 821)5′-CCGGUGAAUCCAAGUGUCCUCUGat-3′ (SEQ ID NO: 54)3′-GUGGCCACUUAGGUUCACAGGAGACUA-5′ (SEQ ID NO: 438) TTR-234 Target:5′-CACCGGTGAATCCAAGTGTCCTCTGAT-3′ (SEQ ID NO: 822)5′-UGAAUCCAAGUGUCCUCUGAUGGtc-3′ (SEQ ID NO: 55)3′-CCACUUAGGUUCACAGGAGACUACCAG-5′ (SEQ ID NO: 439) TTR-238 Target:5′-GGTGAATCCAAGTGTCCTCTGATGGTC-3′ (SEQ ID NO: 823)5′-GAAUCCAAGUGUCCUCUGAUGGUca-3′ (SEQ ID NO: 56)3′-CACUUAGGUUCACAGGAGACUACCAGU-5′ (SEQ ID NO: 440) TTR-239 Target:5′-GTGAATCCAAGTGTCCTCTGATGGTCA-3′ (SEQ ID NO: 824)5′-AAUCCAAGUGUCCUCUGAUGGUCaa-3′ (SEQ ID NO: 57)3′-ACUUAGGUUCACAGGAGACUACCAGUU-5′ (SEQ ID NO: 441) TTR-240 Target:5′-TGAATCCAAGTGTCCTCTGATGGTCAA-3′ (SEQ ID NO: 825)5′-AUCCAAGUGUCCUCUGAUGGUCAaa-3′ (SEQ ID NO: 58)3′-CUUAGGUUCACAGGAGACUACCAGUUU-5′ (SEQ ID NO: 442) TTR-241 Target:5′-GAATCCAAGTGTCCTCTGATGGTCAAA-3′ (SEQ ID NO: 826)5′-UCCAAGUGUCCUCUGAUGGUCAAag-3′ (SEQ ID NO: 59)3′-UUAGGUUCACAGGAGACUACCAGUUUC-5′ (SEQ ID NO: 443) TTR-242 Target:5′-AATCCAAGTGTCCTCTGATGGTCAAAG-3′ (SEQ ID NO: 827)5′-CCAAGUGUCCUCUGAUGGUCAAAgt-3′ (SEQ ID NO: 60)3′-UAGGUUCACAGGAGACUACCAGUUUCA-5′ (SEQ ID NO: 444) TTR-243 Target:5′-ATCCAAGTGTCCTCTGATGGTCAAAGT-3′ (SEQ ID NO: 828)5′-CAAGUGUCCUCUGAUGGUCAAAGtt-3′ (SEQ ID NO: 61)3′-AGGUUCACAGGAGACUACCAGUUUCAA-5′ (SEQ ID NO: 445) TTR-244 Target:5′-TCCAAGTGTCCTCTGATGGTCAAAGTT-3′ (SEQ ID NO: 829)5′-AAGUGUCCUCUGAUGGUCAAAGUtc-3′ (SEQ ID NO: 62)3′-GGUUCACAGGAGACUACCAGUUUCAAG-5′ (SEQ ID NO: 446) TTR-245 Target:5′-CCAAGTGTCCTCTGATGGTCAAAGTTC-3′ (SEQ ID NO: 830)5′-AGUGUCCUCUGAUGGUCAAAGUUct-3′ (SEQ ID NO: 63)3′-GUUCACAGGAGACUACCAGUUUCAAGA-5′ (SEQ ID NO: 447) TTR-246 Target:5′-CAAGTGTCCTCTGATGGTCAAAGTTCT-3′ (SEQ ID NO: 831)5′-GUGUCCUCUGAUGGUCAAAGUUCta-3′ (SEQ ID NO: 64)3′-UUCACAGGAGACUACCAGUUUCAAGAU-5′ (SEQ ID NO: 448) TTR-247 Target:5′-AAGTGTCCTCTGATGGTCAAAGTTCTA-3′ (SEQ ID NO: 832)5′-UGUCCUCUGAUGGUCAAAGUUCUag-3′ (SEQ ID NO: 65)3′-UCACAGGAGACUACCAGUUUCAAGAUC-5′ (SEQ ID NO: 449) TTR-248 Target:5′-AGTGTCCTCTGATGGTCAAAGTTCTAG-3′ (SEQ ID NO: 833)5′-GUCCUCUGAUGGUCAAAGUUCUAga-3′ (SEQ ID NO: 66)3′-CACAGGAGACUACCAGUUUCAAGAUCU-5′ (SEQ ID NO: 450) TTR-249 Target:5′-GTGTCCTCTGATGGTCAAAGTTCTAGA-3′ (SEQ ID NO: 834)5′-UCCUCUGAUGGUCAAAGUUCUAGat-3′ (SEQ ID NO: 67)3′-ACAGGAGACUACCAGUUUCAAGAUCUA-5′ (SEQ ID NO: 451) TTR-250 Target:5′-TGTCCTCTGATGGTCAAAGTTCTAGAT-3′ (SEQ ID NO: 835)5′-CCUCUGAUGGUCAAAGUUCUAGAtg-3′ (SEQ ID NO: 68)3′-CAGGAGACUACCAGUUUCAAGAUCUAC-5′ (SEQ ID NO: 452) TTR-251 Target:5′-GTCCTCTGATGGTCAAAGTTCTAGATG-3′ (SEQ ID NO: 836)5′-CUCUGAUGGUCAAAGUUCUAGAUgc-3′ (SEQ ID NO: 69)3′-AGGAGACUACCAGUUUCAAGAUCUACG-5′ (SEQ ID NO: 453) TTR-252 Target:5′-TCCTCTGATGGTCAAAGTTCTAGATGC-3′ (SEQ ID NO: 837)5′-UCUGAUGGUCAAAGUUCUAGAUGct-3′ (SEQ ID NO: 70)3′-GGAGACUACCAGUUUCAAGAUCUACGA-5′ (SEQ ID NO: 454) TTR-253 Target:5′-CCTCTGATGGTCAAAGTTCTAGATGCT-3′ (SEQ ID NO: 838)5′-CUGAUGGUCAAAGUUCUAGAUGCtg-3′ (SEQ ID NO: 71)3′-GAGACUACCAGUUUCAAGAUCUACGAC-5′ (SEQ ID NO: 455) TTR-254 Target:5′-CTCTGATGGTCAAAGTTCTAGATGCTG-3′ (SEQ ID NO: 839)5′-UGAUGGUCAAAGUUCUAGAUGCUgt-3′ (SEQ ID NO: 72)3′-AGACUACCAGUUUCAAGAUCUACGACA-5′ (SEQ ID NO: 456) TTR-255 Target:5′-TCTGATGGTCAAAGTTCTAGATGCTGT-3′ (SEQ ID NO: 840)5′-GAUGGUCAAAGUUCUAGAUGCUGtc-3′ (SEQ ID NO: 73)3′-GACUACCAGUUUCAAGAUCUACGACAG-5′ (SEQ ID NO: 457) TTR-256 Target:5′-CTGATGGTCAAAGTTCTAGATGCTGTC-3′ (SEQ ID NO: 841)5′-AUGGUCAAAGUUCUAGAUGCUGUcc-3′ (SEQ ID NO: 74)3′-ACUACCAGUUUCAAGAUCUACGACAGG-5′ (SEQ ID NO: 458) TTR-257 Target:5′-TGATGGTCAAAGTTCTAGATGCTGTCC-3′ (SEQ ID NO: 842)5′-UGGUCAAAGUUCUAGAUGCUGUCcg-3′ (SEQ ID NO: 75)3′-CUACCAGUUUCAAGAUCUACGACAGGC-5′ (SEQ ID NO: 459) TTR-258 Target:5′-GATGGTCAAAGTTCTAGATGCTGTCCG-3′ (SEQ ID NO: 843)5′-GCCAUUUGCCUCUGGGAAAACCAgt-3′ (SEQ ID NO: 76)3′-CUCGGUAAACGGAGACCCUUUUGGUCA-5′ (SEQ ID NO: 460) TTR-346 Target:5′-GAGCCATTTGCCTCTGGGAAAACCAGT-3′ (SEQ ID NO: 844)5′-CCAUUUGCCUCUGGGAAAACCAGtg-3′ (SEQ ID NO: 77)3′-UCGGUAAACGGAGACCCUUUUGGUCAC-5′ (SEQ ID NO: 461) TTR-347 Target:5′-AGCCATTTGCCTCTGGGAAAACCAGTG-3′ (SEQ ID NO: 845)5′-CAUUUGCCUCUGGGAAAACCAGUga-3′ (SEQ ID NO: 78)3′-CGGUAAACGGAGACCCUUUUGGUCACU-5′ (SEQ ID NO: 462) TTR-348 Target:5′-GCCATTTGCCTCTGGGAAAACCAGTGA-3′ (SEQ ID NO: 846)5′-AUUUGCCUCUGGGAAAACCAGUGag-3′ (SEQ ID NO: 79)3′-GGUAAACGGAGACCCUUUUGGUCACUC-5′ (SEQ ID NO: 463) TTR-349 Target:5′-CCATTTGCCTCTGGGAAAACCAGTGAG-3′ (SEQ ID NO: 847)5′-UUUGCCUCUGGGAAAACCAGUGAgt-3′ (SEQ ID NO: 80)3′-GUAAACGGAGACCCUUUUGGUCACUCA-5′ (SEQ ID NO: 464) TTR-350 Target:5′-CATTTGCCTCTGGGAAAACCAGTGAGT-3′ (SEQ ID NO: 848)5′-UUGCCUCUGGGAAAACCAGUGAGtc-3′ (SEQ ID NO: 81)3′-UAAACGGAGACCCUUUUGGUCACUCAG-5′ (SEQ ID NO: 465) TTR-351 Target:5′-ATTTGCCTCTGGGAAAACCAGTGAGTC-3′ (SEQ ID NO: 849)5′-UGCCUCUGGGAAAACCAGUGAGUct-3′ (SEQ ID NO: 82)3′-AAACGGAGACCCUUUUGGUCACUCAGA-5′ (SEQ ID NO: 466) TTR-352 Target:5′-TTTGCCTCTGGGAAAACCAGTGAGTCT-3′ (SEQ ID NO: 850)5′-GCCUCUGGGAAAACCAGUGAGUCtg-3′ (SEQ ID NO: 83)3′-AACGGAGACCCUUUUGGUCACUCAGAC-5′ (SEQ ID NO: 467) TTR-353 Target:5′-TTGCCTCTGGGAAAACCAGTGAGTCTG-3′ (SEQ ID NO: 851)5′-CCUCUGGGAAAACCAGUGAGUCUgg-3′ (SEQ ID NO: 84)3′-ACGGAGACCCUUUUGGUCACUCAGACC-5′ (SEQ ID NO: 468) TTR-354 Target:5′-TGCCTCTGGGAAAACCAGTGAGTCTGG-3′ (SEQ ID NO: 852)5′-CUCUGGGAAAACCAGUGAGUCUGga-3′ (SEQ ID NO: 85)3′-CGGAGACCCUUUUGGUCACUCAGACCU-5′ (SEQ ID NO: 469) TTR-355 Target:5′-GCCTCTGGGAAAACCAGTGAGTCTGGA-3′ (SEQ ID NO: 853)5′-UCUGGGAAAACCAGUGAGUCUGGag-3′ (SEQ ID NO: 86)3′-GGAGACCCUUUUGGUCACUCAGACCUC-5′ (SEQ ID NO: 470) TTR-356 Target:5′-CCTCTGGGAAAACCAGTGAGTCTGGAG-3′ (SEQ ID NO: 854)5′-CUGGGAAAACCAGUGAGUCUGGAga-3′ (SEQ ID NO: 87)3′-GAGACCCUUUUGGUCACUCAGACCUCU-5′ (SEQ ID NO: 471) TTR-357 Target:5′-CTCTGGGAAAACCAGTGAGTCTGGAGA-3′ (SEQ ID NO: 855)5′-UGGGAAAACCAGUGAGUCUGGAGag-3′ (SEQ ID NO: 88)3′-AGACCCUUUUGGUCACUCAGACCUCUC-5′ (SEQ ID NO: 472) TTR-358 Target:5′-TCTGGGAAAACCAGTGAGTCTGGAGAG-3′ (SEQ ID NO: 856)5′-GGGAAAACCAGUGAGUCUGGAGAgc-3′ (SEQ ID NO: 89)3′-GACCCUUUUGGUCACUCAGACCUCUCG-5′ (SEQ ID NO: 473) TTR-359 Target:5′-CTGGGAAAACCAGTGAGTCTGGAGAGC-3′ (SEQ ID NO: 857)5′-GGAAAACCAGUGAGUCUGGAGAGct-3′ (SEQ ID NO: 90)3′-ACCCUUUUGGUCACUCAGACCUCUCGA-5′ (SEQ ID NO: 474) TTR-360 Target:5′-TGGGAAAACCAGTGAGTCTGGAGAGCT-3′ (SEQ ID NO: 858)5′-GAAAACCAGUGAGUCUGGAGAGCtg-3′ (SEQ ID NO: 91)3′-CCCUUUUGGUCACUCAGACCUCUCGAC-5′ (SEQ ID NO: 475) TTR-361 Target:5′-GGGAAAACCAGTGAGTCTGGAGAGCTG-3′ (SEQ ID NO: 859)5′-AGCUGCAUGGGCUCACAACUGAGga-3′ (SEQ ID NO: 92)3′-UCUCGACGUACCCGAGUGUUGACUCCU-5′ (SEQ ID NO: 476) TTR-381 Target:5′-AGAGCTGCATGGGCTCACAACTGAGGA-3′ (SEQ ID NO: 860)5′-GCUGCAUGGGCUCACAACUGAGGag-3′ (SEQ ID NO: 93)3′-CUCGACGUACCCGAGUGUUGACUCCUC-5′ (SEQ ID NO: 477) TTR-382 Target:5′-GAGCTGCATGGGCTCACAACTGAGGAG-3′ (SEQ ID NO: 861)5′-CUGCAUGGGCUCACAACUGAGGAgg-3′ (SEQ ID NO: 94)3′-UCGACGUACCCGAGUGUUGACUCCUCC-5′ (SEQ ID NO: 478) TTR-383 Target:5′-AGCTGCATGGGCTCACAACTGAGGAGG-3′ (SEQ ID NO: 862)5′-UGCAUGGGCUCACAACUGAGGAGga-3′ (SEQ ID NO: 95)3′-CGACGUACCCGAGUGUUGACUCCUCCU-5′ (SEQ ID NO: 479) TTR-384 Target:5′-GCTGCATGGGCTCACAACTGAGGAGGA-3′ (SEQ ID NO: 863)5′-GCAUGGGCUCACAACUGAGGAGGaa-3′ (SEQ ID NO: 96)3′-GACGUACCCGAGUGUUGACUCCUCCUU-5′ (SEQ ID NO: 480) TTR-385 Target:5′-CTGCATGGGCTCACAACTGAGGAGGAA-3′ (SEQ ID NO: 864)5′-CAUGGGCUCACAACUGAGGAGGAat-3′ (SEQ ID NO: 97)3′-ACGUACCCGAGUGUUGACUCCUCCUUA-5′ (SEQ ID NO: 481) TTR-386 Target:5′-TGCATGGGCTCACAACTGAGGAGGAAT-3′ (SEQ ID NO: 865)5′-AUGGGCUCACAACUGAGGAGGAAtt-3′ (SEQ ID NO: 98)3′-CGUACCCGAGUGUUGACUCCUCCUUAA-5′ (SEQ ID NO: 482) TTR-387 Target:5′-GCATGGGCTCACAACTGAGGAGGAATT-3′ (SEQ ID NO: 866)5′-UGGGCUCACAACUGAGGAGGAAUtt-3′ (SEQ ID NO: 99)3′-GUACCCGAGUGUUGACUCCUCCUUAAA-5′ (SEQ ID NO: 483) TTR-388 Target:5′-CATGGGCTCACAACTGAGGAGGAATTT-3′ (SEQ ID NO: 867)5′-GGGCUCACAACUGAGGAGGAAUUtg-3′ (SEQ ID NO: 100)3′-UACCCGAGUGUUGACUCCUCCUUAAAC-5′ (SEQ ID NO: 484) TTR-389 Target:5′-ATGGGCTCACAACTGAGGAGGAATTTG-3′ (SEQ ID NO: 868)5′-GGCUCACAACUGAGGAGGAAUUUgt-3′ (SEQ ID NO: 101)3′-ACCCGAGUGUUGACUCCUCCUUAAACA-5′ (SEQ ID NO: 485) TTR-390 Target:5′-TGGGCTCACAACTGAGGAGGAATTTGT-3′ (SEQ ID NO: 869)5′-GCUCACAACUGAGGAGGAAUUUGta-3′ (SEQ ID NO: 102)3′-CCCGAGUGUUGACUCCUCCUUAAACAU-5′ (SEQ ID NO: 486) TTR-391 Target:5′-GGGCTCACAACTGAGGAGGAATTTGTA-3′ (SEQ ID NO: 870)5′-CUCACAACUGAGGAGGAAUUUGUag-3′ (SEQ ID NO: 103)3′-CCGAGUGUUGACUCCUCCUUAAACAUC-5′ (SEQ ID NO: 487) TTR-392 Target:5′-GGCTCACAACTGAGGAGGAATTTGTAG-3′ (SEQ ID NO: 871)5′-UCACAACUGAGGAGGAAUUUGUAga-3′ (SEQ ID NO: 104)3′-CGAGUGUUGACUCCUCCUUAAACAUCU-5′ (SEQ ID NO: 488) TTR-393 Target:5′-GCTCACAACTGAGGAGGAATTTGTAGA-3′ (SEQ ID NO: 872)5′-CACAACUGAGGAGGAAUUUGUAGaa-3′ (SEQ ID NO: 105)3′-GAGUGUUGACUCCUCCUUAAACAUCUU-5′ (SEQ ID NO: 489) TTR-394 Target:5′-CTCACAACTGAGGAGGAATTTGTAGAA-3′ (SEQ ID NO: 873)5′-ACAACUGAGGAGGAAUUUGUAGAag-3′ (SEQ ID NO: 106)3′-AGUGUUGACUCCUCCUUAAACAUCUUC-5′ (SEQ ID NO: 490) TTR-395 Target:5′-TCACAACTGAGGAGGAATTTGTAGAAG-3′ (SEQ ID NO: 874)5′-CAACUGAGGAGGAAUUUGUAGAAgg-3′ (SEQ ID NO: 107)3′-GUGUUGACUCCUCCUUAAACAUCUUCC-5′ (SEQ ID NO: 491) TTR-396 Target:5′-CACAACTGAGGAGGAATTTGTAGAAGG-3′ (SEQ ID NO: 875)5′-ACUGAGGAGGAAUUUGUAGAAGGga-3′ (SEQ ID NO: 108)3′-GUUGACUCCUCCUUAAACAUCUUCCCU-5′ (SEQ ID NO: 492) TTR-398 Target:5′-CAACTGAGGAGGAATTTGTAGAAGGGA-3′ (SEQ ID NO: 876)5′-CUGAGGAGGAAUUUGUAGAAGGGat-3′ (SEQ ID NO: 109)3′-UUGACUCCUCCUUAAACAUCUUCCCUA-5′ (SEQ ID NO: 493) TTR-399 Target:5′-AACTGAGGAGGAATTTGTAGAAGGGAT-3′ (SEQ ID NO: 877)5′-UGAGGAGGAAUUUGUAGAAGGGAta-3′ (SEQ ID NO: 110)3′-UGACUCCUCCUUAAACAUCUUCCCUAU-5′ (SEQ ID NO: 494) TTR-400 Target:5′-ACTGAGGAGGAATTTGTAGAAGGGATA-3′ (SEQ ID NO: 878)5′-GAGGAGGAAUUUGUAGAAGGGAUat-3′ (SEQ ID NO: 111)3′-GACUCCUCCUUAAACAUCUUCCCUAUA-5′ (SEQ ID NO: 495) TTR-401 Target:5′-CTGAGGAGGAATTTGTAGAAGGGATAT-3′ (SEQ ID NO: 879)5′-AGGAGGAAUUUGUAGAAGGGAUAta-3′ (SEQ ID NO: 112)3′-ACUCCUCCUUAAACAUCUUCCCUAUAU-5′ (SEQ ID NO: 496) TTR-402 Target:5′-TGAGGAGGAATTTGTAGAAGGGATATA-3′ (SEQ ID NO: 880)5′-GGAGGAAUUUGUAGAAGGGAUAUac-3′ (SEQ ID NO: 113)3′-CUCCUCCUUAAACAUCUUCCCUAUAUG-5′ (SEQ ID NO: 497) TTR-403 Target:5′-GAGGAGGAATTTGTAGAAGGGATATAC-3′ (SEQ ID NO: 881)5′-GAGGAAUUUGUAGAAGGGAUAUAca-3′ (SEQ ID NO: 114)3′-UCCUCCUUAAACAUCUUCCCUAUAUGU-5′ (SEQ ID NO: 498) TTR-404 Target:5′-AGGAGGAATTTGTAGAAGGGATATACA-3′ (SEQ ID NO: 882)5′-AGGAAUUUGUAGAAGGGAUAUACaa-3′ (SEQ ID NO: 115)3′-CCUCCUUAAACAUCUUCCCUAUAUGUU-5′ (SEQ ID NO: 499) TTR-405 Target:5′-GGAGGAATTTGTAGAAGGGATATACAA-3′ (SEQ ID NO: 883)5′-GGAAUUUGUAGAAGGGAUAUACAaa-3′ (SEQ ID NO: 116)3′-CUCCUUAAACAUCUUCCCUAUAUGUUU-5′ (SEQ ID NO: 500) TTR-406 Target:5′-GAGGAATTTGTAGAAGGGATATACAAA-3′ (SEQ ID NO: 884)5′-GAAUUUGUAGAAGGGAUAUACAAag-3′ (SEQ ID NO: 117)3′-UCCUUAAACAUCUUCCCUAUAUGUUUC-5′ (SEQ ID NO: 501) TTR-407 Target:5′-AGGAATTTGTAGAAGGGATATACAAAG-3′ (SEQ ID NO: 885)5′-AAUUUGUAGAAGGGAUAUACAAAgt-3′ (SEQ ID NO: 118)3′-CCUUAAACAUCUUCCCUAUAUGUUUCA-5′ (SEQ ID NO: 502) TTR-408 Target:5′-GGAATTTGTAGAAGGGATATACAAAGT-3′ (SEQ ID NO: 886)5′-AUUUGUAGAAGGGAUAUACAAAGtg-3′ (SEQ ID NO: 119)3′-CUUAAACAUCUUCCCUAUAUGUUUCAC-5′ (SEQ ID NO: 503) TTR-409 Target:5′-GAATTTGTAGAAGGGATATACAAAGTG-3′ (SEQ ID NO: 887)5′-UUUGUAGAAGGGAUAUACAAAGUgg-3′ (SEQ ID NO: 120)3′-UUAAACAUCUUCCCUAUAUGUUUCACC-5′ (SEQ ID NO: 504) TTR-410 Target:5′-AATTTGTAGAAGGGATATACAAAGTGG-3′ (SEQ ID NO: 888)5′-UUGUAGAAGGGAUAUACAAAGUGga-3′ (SEQ ID NO: 121)3′-UAAACAUCUUCCCUAUAUGUUUCACCU-5′ (SEQ ID NO: 505) TTR-411 Target:5′-ATTTGTAGAAGGGATATACAAAGTGGA-3′ (SEQ ID NO: 889)5′-UGUAGAAGGGAUAUACAAAGUGGaa-3′ (SEQ ID NO: 122)3′-AAACAUCUUCCCUAUAUGUUUCACCUU-5′ (SEQ ID NO: 506) TTR-412 Target:5′-TTTGTAGAAGGGATATACAAAGTGGAA-3′ (SEQ ID NO: 890)5′-GUAGAAGGGAUAUACAAAGUGGAaa-3′ (SEQ ID NO: 123)3′-AACAUCUUCCCUAUAUGUUUCACCUUU-5′ (SEQ ID NO: 507) TTR-413 Target:5′-TTGTAGAAGGGATATACAAAGTGGAAA-3′ (SEQ ID NO: 891)5′-UAGAAGGGAUAUACAAAGUGGAAat-3′ (SEQ ID NO: 124)3′-ACAUCUUCCCUAUAUGUUUCACCUUUA-5′ (SEQ ID NO: 508) TTR-414 Target:5′-TGTAGAAGGGATATACAAAGTGGAAAT-3′ (SEQ ID NO: 892)5′-AGAAGGGAUAUACAAAGUGGAAAta-3′ (SEQ ID NO: 125)3′-CAUCUUCCCUAUAUGUUUCACCUUUAU-5′ (SEQ ID NO: 509) TTR-415 Target:5′-GTAGAAGGGATATACAAAGTGGAAATA-3′ (SEQ ID NO: 893)5′-GAAGGGAUAUACAAAGUGGAAAUag-3′ (SEQ ID NO: 126)3′-AUCUUCCCUAUAUGUUUCACCUUUAUC-5′ (SEQ ID NO: 510) TTR-416 Target:5′-TAGAAGGGATATACAAAGTGGAAATAG-3′ (SEQ ID NO: 894)5′-AAGGGAUAUACAAAGUGGAAAUAga-3′ (SEQ ID NO: 127)3′-UCUUCCCUAUAUGUUUCACCUUUAUCU-5′ (SEQ ID NO: 511) TTR-417 Target:5′-AGAAGGGATATACAAAGTGGAAATAGA-3′ (SEQ ID NO: 895)5′-AGGGAUAUACAAAGUGGAAAUAGac-3′ (SEQ ID NO: 128)3′-CUUCCCUAUAUGUUUCACCUUUAUCUG-5′ (SEQ ID NO: 512) TTR-418 Target:5′-GAAGGGATATACAAAGTGGAAATAGAC-3′ (SEQ ID NO: 896)5′-GGGAUAUACAAAGUGGAAAUAGAca-3′ (SEQ ID NO: 129)3′-UUCCCUAUAUGUUUCACCUUUAUCUGU-5′ (SEQ ID NO: 513) TTR-419 Target:5′-AAGGGATATACAAAGTGGAAATAGACA-3′ (SEQ ID NO: 897)5′-GGAUAUACAAAGUGGAAAUAGACac-3′ (SEQ ID NO: 130)3′-UCCCUAUAUGUUUCACCUUUAUCUGUG-5′ (SEQ ID NO: 514) TTR-420 Target:5′-AGGGATATACAAAGTGGAAATAGACAC-3′ (SEQ ID NO: 898)5′-GAUAUACAAAGUGGAAAUAGACAcc-3′ (SEQ ID NO: 131)3′-CCCUAUAUGUUUCACCUUUAUCUGUGG-5′ (SEQ ID NO: 515) TTR-421 Target:5′-GGGATATACAAAGTGGAAATAGACACC-3′ (SEQ ID NO: 899)5′-AUAUACAAAGUGGAAAUAGACACca-3′ (SEQ ID NO: 132)3′-CCUAUAUGUUUCACCUUUAUCUGUGGU-5′ (SEQ ID NO: 516) TTR-422 Target:5′-GGATATACAAAGTGGAAATAGACACCA-3′ (SEQ ID NO: 900)5′-UAUACAAAGUGGAAAUAGACACCaa-3′ (SEQ ID NO: 133)3′-CUAUAUGUUUCACCUUUAUCUGUGGUU-5′ (SEQ ID NO: 517) TTR-423 Target:5′-GATATACAAAGTGGAAATAGACACCAA-3′ (SEQ ID NO: 901)5′-AUACAAAGUGGAAAUAGACACCAaa-3′ (SEQ ID NO: 134)3′-UAUAUGUUUCACCUUUAUCUGUGGUUU-5′ (SEQ ID NO: 518) TTR-424 Target:5′-ATATACAAAGTGGAAATAGACACCAAA-3′ (SEQ ID NO: 902)5′-UACAAAGUGGAAAUAGACACCAAat-3′ (SEQ ID NO: 135)3′-AUAUGUUUCACCUUUAUCUGUGGUUUA-5′ (SEQ ID NO: 519) TTR-425 Target:5′-TATACAAAGTGGAAATAGACACCAAAT-3′ (SEQ ID NO: 903)5′-ACAAAGUGGAAAUAGACACCAAAtc-3′ (SEQ ID NO: 136)3′-UAUGUUUCACCUUUAUCUGUGGUUUAG-5′ (SEQ ID NO: 520) TTR-426 Target:5′-ATACAAAGTGGAAATAGACACCAAATC-3′ (SEQ ID NO: 904)5′-CAAAGUGGAAAUAGACACCAAAUct-3′ (SEQ ID NO: 137)3′-AUGUUUCACCUUUAUCUGUGGUUUAGA-5′ (SEQ ID NO: 521) TTR-427 Target:5′-TACAAAGTGGAAATAGACACCAAATCT-3′ (SEQ ID NO: 905)5′-AAAGUGGAAAUAGACACCAAAUCtt-3′ (SEQ ID NO: 138)3′-UGUUUCACCUUUAUCUGUGGUUUAGAA-5′ (SEQ ID NO: 522) TTR-428 Target:5′-ACAAAGTGGAAATAGACACCAAATCTT-3′ (SEQ ID NO: 906)5′-AAGUGGAAAUAGACACCAAAUCUta-3′ (SEQ ID NO: 139)3′-GUUUCACCUUUAUCUGUGGUUUAGAAU-5′ (SEQ ID NO: 523) TTR-429 Target:5′-CAAAGTGGAAATAGACACCAAATCTTA-3′ (SEQ ID NO: 907)5′-AGUGGAAAUAGACACCAAAUCUUac-3′ (SEQ ID NO: 140)3′-UUUCACCUUUAUCUGUGGUUUAGAAUG-5′ (SEQ ID NO: 524) TTR-430 Target:5′-AAAGTGGAAATAGACACCAAATCTTAC-3′ (SEQ ID NO: 908)5′-GUGGAAAUAGACACCAAAUCUUAct-3′ (SEQ ID NO: 141)3′-UUCACCUUUAUCUGUGGUUUAGAAUGA-5′ (SEQ ID NO: 525) TTR-431 Target:5′-AAGTGGAAATAGACACCAAATCTTACT-3′ (SEQ ID NO: 909)5′-UGGAAAUAGACACCAAAUCUUACtg-3′ (SEQ ID NO: 142)3′-UCACCUUUAUCUGUGGUUUAGAAUGAC-5′ (SEQ ID NO: 526) TTR-432 Target:5′-AGTGGAAATAGACACCAAATCTTACTG-3′ (SEQ ID NO: 910)5′-GGAAAUAGACACCAAAUCUUACUgg-3′ (SEQ ID NO: 143)3′-CACCUUUAUCUGUGGUUUAGAAUGACC-5′ (SEQ ID NO: 527) TTR-433 Target:5′-GTGGAAATAGACACCAAATCTTACTGG-3′ (SEQ ID NO: 911)5′-GAAAUAGACACCAAAUCUUACUGga-3′ (SEQ ID NO: 144)3′-ACCUUUAUCUGUGGUUUAGAAUGACCU-5′ (SEQ ID NO: 528) TTR-434 Target:5′-TGGAAATAGACACCAAATCTTACTGGA-3′ (SEQ ID NO: 912)5′-AAAUAGACACCAAAUCUUACUGGaa-3′ (SEQ ID NO: 145)3′-CCUUUAUCUGUGGUUUAGAAUGACCUU-5′ (SEQ ID NO: 529) TTR-435 Target:5′-GGAAATAGACACCAAATCTTACTGGAA-3′ (SEQ ID NO: 913)5′-AAUAGACACCAAAUCUUACUGGAag-3′ (SEQ ID NO: 146)3′-CUUUAUCUGUGGUUUAGAAUGACCUUC-5′ (SEQ ID NO: 530) TTR-436 Target:5′-GAAATAGACACCAAATCTTACTGGAAG-3′ (SEQ ID NO: 914)5′-AUAGACACCAAAUCUUACUGGAAgg-3′ (SEQ ID NO: 147)3′-UUUAUCUGUGGUUUAGAAUGACCUUCC-5′ (SEQ ID NO: 531) TTR-437 Target:5′-AAATAGACACCAAATCTTACTGGAAGG-3′ (SEQ ID NO: 915)5′-AGACACCAAAUCUUACUGGAAGGca-3′ (SEQ ID NO: 148)3′-UAUCUGUGGUUUAGAAUGACCUUCCGU-5′ (SEQ ID NO: 532) TTR-439 Target:5′-ATAGACACCAAATCTTACTGGAAGGCA-3′ (SEQ ID NO: 916)5′-GACACCAAAUCUUACUGGAAGGCac-3′ (SEQ ID NO: 149)3′-AUCUGUGGUUUAGAAUGACCUUCCGUG-5′ (SEQ ID NO: 533) TTR-440 Target:5′-TAGACACCAAATCTTACTGGAAGGCAC-3′ (SEQ ID NO: 917)5′-CACUUGGCAUCUCCCCAUUCCAUga-3′ (SEQ ID NO: 150)3′-CCGUGAACCGUAGAGGGGUAAGGUACU-5′ (SEQ ID NO: 534) TTR-462 Target:5′-GGCACTTGGCATCTCCCCATTCCATGA-3′ (SEQ ID NO: 918)5′-ACUUGGCAUCUCCCCAUUCCAUGag-3′ (SEQ ID NO: 151)3′-CGUGAACCGUAGAGGGGUAAGGUACUC-5′ (SEQ ID NO: 535) TTR-463 Target:5′-GCACTTGGCATCTCCCCATTCCATGAG-3′ (SEQ ID NO: 919)5′-CUUGGCAUCUCCCCAUUCCAUGAgc-3′ (SEQ ID NO: 152)3′-GUGAACCGUAGAGGGGUAAGGUACUCG-5′ (SEQ ID NO: 536) TTR-464 Target:5′-CACTTGGCATCTCCCCATTCCATGAGC-3′ (SEQ ID NO: 920)5′-UUGGCAUCUCCCCAUUCCAUGAGca-3′ (SEQ ID NO: 153)3′-UGAACCGUAGAGGGGUAAGGUACUCGU-5′ (SEQ ID NO: 537) TTR-465 Target:5′-ACTTGGCATCTCCCCATTCCATGAGCA-3′ (SEQ ID NO: 921)5′-UGGCAUCUCCCCAUUCCAUGAGCat-3′ (SEQ ID NO: 154)3′-GAACCGUAGAGGGGUAAGGUACUCGUA-5′ (SEQ ID NO: 538) TTR-466 Target:5′-CTTGGCATCTCCCCATTCCATGAGCAT-3′ (SEQ ID NO: 922)5′-GGCAUCUCCCCAUUCCAUGAGCAtg-3′ (SEQ ID NO: 155)3′-AACCGUAGAGGGGUAAGGUACUCGUAC-5′ (SEQ ID NO: 539) TTR-467 Target:5′-TTGGCATCTCCCCATTCCATGAGCATG-3′ (SEQ ID NO: 923)5′-GCAUCUCCCCAUUCCAUGAGCAUgc-3′ (SEQ ID NO: 156)3′-ACCGUAGAGGGGUAAGGUACUCGUACG-5′ (SEQ ID NO: 540) TTR-468 Target:5′-TGGCATCTCCCCATTCCATGAGCATGC-3′ (SEQ ID NO: 924)5′-CAUCUCCCCAUUCCAUGAGCAUGca-3′ (SEQ ID NO: 157)3′-CCGUAGAGGGGUAAGGUACUCGUACGU-5′ (SEQ ID NO: 541) TTR-469 Target:5′-GGCATCTCCCCATTCCATGAGCATGCA-3′ (SEQ ID NO: 925)5′-AUCUCCCCAUUCCAUGAGCAUGCag-3′ (SEQ ID NO: 158)3′-CGUAGAGGGGUAAGGUACUCGUACGUC-5′ (SEQ ID NO: 542) TTR-470 Target:5′-GCATCTCCCCATTCCATGAGCATGCAG-3′ (SEQ ID NO: 926)5′-UCUCCCCAUUCCAUGAGCAUGCAga-3′ (SEQ ID NO: 159)3′-GUAGAGGGGUAAGGUACUCGUACGUCU-5′ (SEQ ID NO: 543) TTR-471 Target:5′-CATCTCCCCATTCCATGAGCATGCAGA-3′ (SEQ ID NO: 927)5′-CUCCCCAUUCCAUGAGCAUGCAGag-3′ (SEQ ID NO: 160)3′-UAGAGGGGUAAGGUACUCGUACGUCUC-5′ (SEQ ID NO: 544) TTR-472 Target:5′-ATCTCCCCATTCCATGAGCATGCAGAG-3′ (SEQ ID NO: 928)5′-UCCCCAUUCCAUGAGCAUGCAGAgg-3′ (SEQ ID NO: 161)3′-AGAGGGGUAAGGUACUCGUACGUCUCC-5′ (SEQ ID NO: 545) TTR-473 Target:5′-TCTCCCCATTCCATGAGCATGCAGAGG-3′ (SEQ ID NO: 929)5′-CCCCAUUCCAUGAGCAUGCAGAGgt-3′ (SEQ ID NO: 162)3′-GAGGGGUAAGGUACUCGUACGUCUCCA-5′ (SEQ ID NO: 546) TTR-474 Target:5′-CTCCCCATTCCATGAGCATGCAGAGGT-3′ (SEQ ID NO: 930)5′-CAUGAGCAUGCAGAGGUGGUAUUca-3′ (SEQ ID NO: 163)3′-AGGUACUCGUACGUCUCCACCAUAAGU-5′ (SEQ ID NO: 547) TTR-482 Target:5′-TCCATGAGCATGCAGAGGTGGTATTCA-3′ (SEQ ID NO: 931)5′-AUGAGCAUGCAGAGGUGGUAUUCac-3′ (SEQ ID NO: 164)3′-GGUACUCGUACGUCUCCACCAUAAGUG-5′ (SEQ ID NO: 548) TTR-483 Target:5′-CCATGAGCATGCAGAGGTGGTATTCAC-3′ (SEQ ID NO: 932)5′-UGAGCAUGCAGAGGUGGUAUUCAca-3′ (SEQ ID NO: 165)3′-GUACUCGUACGUCUCCACCAUAAGUGU-5′ (SEQ ID NO: 549) TTR-484 Target:5′-CATGAGCATGCAGAGGTGGTATTCACA-3′ (SEQ ID NO: 933)5′-GAGCAUGCAGAGGUGGUAUUCACag-3′ (SEQ ID NO: 166)3′-UACUCGUACGUCUCCACCAUAAGUGUC-5′ (SEQ ID NO: 550) TTR-485 Target:5′-ATGAGCATGCAGAGGTGGTATTCACAG-3′ (SEQ ID NO: 934)5′-AUGCAGAGGUGGUAUUCACAGCCaa-3′ (SEQ ID NO: 167)3′-CGUACGUCUCCACCAUAAGUGUCGGUU-5′ (SEQ ID NO: 551) TTR-489 Target:5′-GCATGCAGAGGTGGTATTCACAGCCAA-3′ (SEQ ID NO: 935)5′-AGAGGUGGUAUUCACAGCCAACGac-3′ (SEQ ID NO: 168)3′-CGUCUCCACCAUAAGUGUCGGUUGCUG-5′ (SEQ ID NO: 552) TTR-493 Target:5′-GCAGAGGTGGTATTCACAGCCAACGAC-3′ (SEQ ID NO: 936)5′-GAGGUGGUAUUCACAGCCAACGAct-3′ (SEQ ID NO: 169)3′-GUCUCCACCAUAAGUGUCGGUUGCUGA-5′ (SEQ ID NO: 553) TTR-494 Target:5′-CAGAGGTGGTATTCACAGCCAACGACT-3′ (SEQ ID NO: 937)5′-GUCGUCACCAAUCCCAAGGAAUGag-3′ (SEQ ID NO: 170)3′-GACAGCAGUGGUUAGGGUUCCUUACUC-5′ (SEQ ID NO: 554) TTR-581 Target:5′-CTGTCGTCACCAATCCCAAGGAATGAG-3′ (SEQ ID NO: 938)5′-GGACGAGGGAUGGGAUUUCAUGUaa-3′ (SEQ ID NO: 171)3′-UUCCUGCUCCCUACCCUAAAGUACAUU-5′ (SEQ ID NO: 555) TTR-631 Target:5′-AAGGACGAGGGATGGGATTTCATGTAA-3′ (SEQ ID NO: 939)5′-GACGAGGGAUGGGAUUUCAUGUAac-3′ (SEQ ID NO: 172)3′-UCCUGCUCCCUACCCUAAAGUACAUUG-5′ (SEQ ID NO: 556) TTR-632 Target:5′-AGGACGAGGGATGGGATTTCATGTAAC-3′ (SEQ ID NO: 940)5′-GAGGGAUGGGAUUUCAUGUAACCaa-3′ (SEQ ID NO: 173)3′-UGCUCCCUACCCUAAAGUACAUUGGUU-5′ (SEQ ID NO: 557) TTR-635 Target:5′-ACGAGGGATGGGATTTCATGTAACCAA-3′ (SEQ ID NO: 941)5′-AGGGAUGGGAUUUCAUGUAACCAag-3′ (SEQ ID NO: 174)3′-GCUCCCUACCCUAAAGUACAUUGGUUC-5′ (SEQ ID NO: 558) TTR-636 Target:5′-CGAGGGATGGGATTTCATGTAACCAAG-3′ (SEQ ID NO: 942)5′-GGGAUGGGAUUUCAUGUAACCAAga-3′ (SEQ ID NO: 175)3′-CUCCCUACCCUAAAGUACAUUGGUUCU-5′ (SEQ ID NO: 559) TTR-637 Target:5′-GAGGGATGGGATTTCATGTAACCAAGA-3′ (SEQ ID NO: 943)5′-GAUGGGAUUUCAUGUAACCAAGAgt-3′ (SEQ ID NO: 176)3′-CCCUACCCUAAAGUACAUUGGUUCUCA-5′ (SEQ ID NO: 560) TTR-639 Target:5′-GGGATGGGATTTCATGTAACCAAGAGT-3′ (SEQ ID NO: 944)5′-AUGGGAUUUCAUGUAACCAAGAGta-3′ (SEQ ID NO: 177)3′-CCUACCCUAAAGUACAUUGGUUCUCAU-5′ (SEQ ID NO: 561) TTR-640 Target:5′-GGATGGGATTTCATGTAACCAAGAGTA-3′ (SEQ ID NO: 945)5′-UGGGAUUUCAUGUAACCAAGAGUat-3′ (SEQ ID NO: 178)3′-CUACCCUAAAGUACAUUGGUUCUCAUA-5′ (SEQ ID NO: 562) TTR-641 Target:5′-GATGGGATTTCATGTAACCAAGAGTAT-3′ (SEQ ID NO: 946)5′-GGGAUUUCAUGUAACCAAGAGUAtt-3′ (SEQ ID NO: 179)3′-UACCCUAAAGUACAUUGGUUCUCAUAA-5′ (SEQ ID NO: 563) TTR-642 Target:5′-ATGGGATTTCATGTAACCAAGAGTATT-3′ (SEQ ID NO: 947)5′-GGAUUUCAUGUAACCAAGAGUAUtc-3′ (SEQ ID NO: 180)3′-ACCCUAAAGUACAUUGGUUCUCAUAAG-5′ (SEQ ID NO: 564) TTR-643 Target:5′-TGGGATTTCATGTAACCAAGAGTATTC-3′ (SEQ ID NO: 948)5′-GAUUUCAUGUAACCAAGAGUAUUcc-3′ (SEQ ID NO: 181)3′-CCCUAAAGUACAUUGGUUCUCAUAAGG-5′ (SEQ ID NO: 565) TTR-644 Target:5′-GGGATTTCATGTAACCAAGAGTATTCC-3′ (SEQ ID NO: 949)5′-AUUUCAUGUAACCAAGAGUAUUCca-3′ (SEQ ID NO: 182)3′-CCUAAAGUACAUUGGUUCUCAUAAGGU-5′ (SEQ ID NO: 566) TTR-645 Target:5′-GGATTTCATGTAACCAAGAGTATTCCA-3′ (SEQ ID NO: 950)5′-UUUCAUGUAACCAAGAGUAUUCCat-3′ (SEQ ID NO: 183)3′-CUAAAGUACAUUGGUUCUCAUAAGGUA-5′ (SEQ ID NO: 567) TTR-646 Target:5′-GATTTCATGTAACCAAGAGTATTCCAT-3′ (SEQ ID NO: 951)5′-UUCAUGUAACCAAGAGUAUUCCAtt-3′ (SEQ ID NO: 184)3′-UAAAGUACAUUGGUUCUCAUAAGGUAA-5′ (SEQ ID NO: 568) TTR-647 Target:5′-ATTTCATGTAACCAAGAGTATTCCATT-3′ (SEQ ID NO: 952)5′-UCAUGUAACCAAGAGUAUUCCAUtt-3′ (SEQ ID NO: 185)3′-AAAGUACAUUGGUUCUCAUAAGGUAAA-5′ (SEQ ID NO: 569) TTR-648 Target:5′-TTTCATGTAACCAAGAGTATTCCATTT-3′ (SEQ ID NO: 953)5′-CAUGUAACCAAGAGUAUUCCAUUtt-3′ (SEQ ID NO: 186)3′-AAGUACAUUGGUUCUCAUAAGGUAAAA-5′ (SEQ ID NO: 570) TTR-649 Target:5′-TTCATGTAACCAAGAGTATTCCATTTT-3′ (SEQ ID NO: 954)5′-AUGUAACCAAGAGUAUUCCAUUUtt-3′ (SEQ ID NO: 187)3′-AGUACAUUGGUUCUCAUAAGGUAAAAA-5′ (SEQ ID NO: 571) TTR-650 Target:5′-TCATGTAACCAAGAGTATTCCATTTTT-3′ (SEQ ID NO: 955)5′-UGUAACCAAGAGUAUUCCAUUUUta-3′ (SEQ ID NO: 188)3′-GUACAUUGGUUCUCAUAAGGUAAAAAU-5′ (SEQ ID NO: 572) TTR-651 Target:5′-CATGTAACCAAGAGTATTCCATTTTTA-3′ (SEQ ID NO: 956)5′-GUAACCAAGAGUAUUCCAUUUUUac-3′ (SEQ ID NO: 189)3′-UACAUUGGUUCUCAUAAGGUAAAAAUG-5′ (SEQ ID NO: 573) TTR-652 Target:5′-ATGTAACCAAGAGTATTCCATTTTTAC-3′ (SEQ ID NO: 957)5′-UAACCAAGAGUAUUCCAUUUUUAct-3′ (SEQ ID NO: 190)3′-ACAUUGGUUCUCAUAAGGUAAAAAUGA-5′ (SEQ ID NO: 574) TTR-653 Target:5′-TGTAACCAAGAGTATTCCATTTTTACT-3′ (SEQ ID NO: 958)5′-AACCAAGAGUAUUCCAUUUUUACta-3′ (SEQ ID NO: 191)3′-CAUUGGUUCUCAUAAGGUAAAAAUGAU-5′ (SEQ ID NO: 575) TTR-654 Target:5′-GTAACCAAGAGTATTCCATTTTTACTA-3′ (SEQ ID NO: 959)5′-ACCAAGAGUAUUCCAUUUUUACUaa-3′ (SEQ ID NO: 192)3′-AUUGGUUCUCAUAAGGUAAAAAUGAUU-5′ (SEQ ID NO: 576) TTR-655 Target:5′-TAACCAAGAGTATTCCATTTTTACTAA-3′ (SEQ ID NO: 960)5′-CCAAGAGUAUUCCAUUUUUACUAaa-3′ (SEQ ID NO: 193)3′-UUGGUUCUCAUAAGGUAAAAAUGAUUU-5′ (SEQ ID NO: 577) TTR-656 Target:5′-AACCAAGAGTATTCCATTTTTACTAAA-3′ (SEQ ID NO: 961)5′-CAAGAGUAUUCCAUUUUUACUAAag-3′ (SEQ ID NO: 194)3′-UGGUUCUCAUAAGGUAAAAAUGAUUUC-5′ (SEQ ID NO: 578) TTR-657 Target:5′-ACCAAGAGTATTCCATTTTTACTAAAG-3′ (SEQ ID NO: 962)5′-AAGAGUAUUCCAUUUUUACUAAAgc-3′ (SEQ ID NO: 195)3′-GGUUCUCAUAAGGUAAAAAUGAUUUCG-5′ (SEQ ID NO: 579) TTR-658 Target:5′-CCAAGAGTATTCCATTTTTACTAAAGC-3′ (SEQ ID NO: 963)5′-AGAGUAUUCCAUUUUUACUAAAGca-3′ (SEQ ID NO: 196)3′-GUUCUCAUAAGGUAAAAAUGAUUUCGU-5′ (SEQ ID NO: 580) TTR-659 Target:5′-CAAGAGTATTCCATTTTTACTAAAGCA-3′ (SEQ ID NO: 964)5′-GAGUAUUCCAUUUUUACUAAAGCag-3′ (SEQ ID NO: 197)3′-UUCUCAUAAGGUAAAAAUGAUUUCGUC-5′ (SEQ ID NO: 581) TTR-660 Target:5′-AAGAGTATTCCATTTTTACTAAAGCAG-3′ (SEQ ID NO: 965)5′-AGUAUUCCAUUUUUACUAAAGCAgt-3′ (SEQ ID NO: 198)3′-UCUCAUAAGGUAAAAAUGAUUUCGUCA-5′ (SEQ ID NO: 582) TTR-661 Target:5′-AGAGTATTCCATTTTTACTAAAGCAGT-3′ (SEQ ID NO: 966)5′-GUAUUCCAUUUUUACUAAAGCAGtg-3′ (SEQ ID NO: 199)3′-CUCAUAAGGUAAAAAUGAUUUCGUCAC-5′ (SEQ ID NO: 583) TTR-662 Target:5′-GAGTATTCCATTTTTACTAAAGCAGTG-3′ (SEQ ID NO: 967)5′-UAUUCCAUUUUUACUAAAGCAGUgt-3′ (SEQ ID NO: 200)3′-UCAUAAGGUAAAAAUGAUUUCGUCACA-5′ (SEQ ID NO: 584) TTR-663 Target:5′-AGTATTCCATTTTTACTAAAGCAGTGT-3′ (SEQ ID NO: 968)5′-AUUCCAUUUUUACUAAAGCAGUGtt-3′ (SEQ ID NO: 201)3′-CAUAAGGUAAAAAUGAUUUCGUCACAA-5′ (SEQ ID NO: 585) TTR-664 Target:5′-GTATTCCATTTTTACTAAAGCAGTGTT-3′ (SEQ ID NO: 969)5′-UUCCAUUUUUACUAAAGCAGUGUtt-3′ (SEQ ID NO: 202)3′-AUAAGGUAAAAAUGAUUUCGUCACAAA-5′ (SEQ ID NO: 586) TTR-665 Target:5′-TATTCCATTTTTACTAAAGCAGTGTTT-3′ (SEQ ID NO: 970)5′-UCCAUUUUUACUAAAGCAGUGUUtt-3′ (SEQ ID NO: 203)3′-UAAGGUAAAAAUGAUUUCGUCACAAAA-5′ (SEQ ID NO: 587) TTR-666 Target:5′-ATTCCATTTTTACTAAAGCAGTGTTTT-3′ (SEQ ID NO: 971)5′-CCAUUUUUACUAAAGCAGUGUUUtc-3′ (SEQ ID NO: 204)3′-AAGGUAAAAAUGAUUUCGUCACAAAAG-5′ (SEQ ID NO: 588) TTR-667 Target:5′-TTCCATTTTTACTAAAGCAGTGTTTTC-3′ (SEQ ID NO: 972)5′-CAUUUUUACUAAAGCAGUGUUUUca-3′ (SEQ ID NO: 205)3′-AGGUAAAAAUGAUUUCGUCACAAAAGU-5′ (SEQ ID NO: 589) TTR-668 Target:5′-TCCATTTTTACTAAAGCAGTGTTTTCA-3′ (SEQ ID NO: 973)5′-AUUUUUACUAAAGCAGUGUUUUCac-3′ (SEQ ID NO: 206)3′-GGUAAAAAUGAUUUCGUCACAAAAGUG-5′ (SEQ ID NO: 590) TTR-669 Target:5′-CCATTTTTACTAAAGCAGTGTTTTCAC-3′ (SEQ ID NO: 974)5′-UUUUUACUAAAGCAGUGUUUUCAcc-3′ (SEQ ID NO: 207)3′-GUAAAAAUGAUUUCGUCACAAAAGUGG-5′ (SEQ ID NO: 591) TTR-670 Target:5′-CATTTTTACTAAAGCAGTGTTTTCACC-3′ (SEQ ID NO: 975)5′-UUUUACUAAAGCAGUGUUUUCACct-3′ (SEQ ID NO: 208)3′-UAAAAAUGAUUUCGUCACAAAAGUGGA-5′ (SEQ ID NO: 592) TTR-671 Target:5′-ATTTTTACTAAAGCAGTGTTTTCACCT-3′ (SEQ ID NO: 976)5′-UUUACUAAAGCAGUGUUUUCACCtc-3′ (SEQ ID NO: 209)3′-AAAAAUGAUUUCGUCACAAAAGUGGAG-5′ (SEQ ID NO: 593) TTR-672 Target:5′-TTTTTACTAAAGCAGTGTTTTCACCTC-3′ (SEQ ID NO: 977)5′-UUACUAAAGCAGUGUUUUCACCUca-3′ (SEQ ID NO: 210)3′-AAAAUGAUUUCGUCACAAAAGUGGAGU-5′ (SEQ ID NO: 594) TTR-673 Target:5′-TTTTACTAAAGCAGTGTTTTCACCTCA-3′ (SEQ ID NO: 978)5′-UACUAAAGCAGUGUUUUCACCUCat-3′ (SEQ ID NO: 211)3′-AAAUGAUUUCGUCACAAAAGUGGAGUA-5′ (SEQ ID NO: 595) TTR-674 Target:5′-TTTACTAAAGCAGTGTTTTCACCTCAT-3′ (SEQ ID NO: 979)5′-ACUAAAGCAGUGUUUUCACCUCAta-3′ (SEQ ID NO: 212)3′-AAUGAUUUCGUCACAAAAGUGGAGUAU-5′ (SEQ ID NO: 596) TTR-675 Target:5′-TTACTAAAGCAGTGTTTTCACCTCATA-3′ (SEQ ID NO: 980)5′-CUAAAGCAGUGUUUUCACCUCAUat-3′ (SEQ ID NO: 213)3′-AUGAUUUCGUCACAAAAGUGGAGUAUA-5′ (SEQ ID NO: 597) TTR-676 Target:5′-TACTAAAGCAGTGTTTTCACCTCATAT-3′ (SEQ ID NO: 981)5′-UAAAGCAGUGUUUUCACCUCAUAtg-3′ (SEQ ID NO: 214)3′-UGAUUUCGUCACAAAAGUGGAGUAUAC-5′ (SEQ ID NO: 598) TTR-677 Target:5′-ACTAAAGCAGTGTTTTCACCTCATATG-3′ (SEQ ID NO: 982)5′-AAAGCAGUGUUUUCACCUCAUAUgc-3′ (SEQ ID NO: 215)3′-GAUUUCGUCACAAAAGUGGAGUAUACG-5′ (SEQ ID NO: 599) TTR-678 Target:5′-CTAAAGCAGTGTTTTCACCTCATATGC-3′ (SEQ ID NO: 983)5′-AAGCAGUGUUUUCACCUCAUAUGct-3′ (SEQ ID NO: 216)3′-AUUUCGUCACAAAAGUGGAGUAUACGA-5′ (SEQ ID NO: 600) TTR-679 Target:5′-TAAAGCAGTGTTTTCACCTCATATGCT-3′ (SEQ ID NO: 984)5′-AGCAGUGUUUUCACCUCAUAUGCta-3′ (SEQ ID NO: 217)3′-UUUCGUCACAAAAGUGGAGUAUACGAU-5′ (SEQ ID NO: 601) TTR-680 Target:5′-AAAGCAGTGTTTTCACCTCATATGCTA-3′ (SEQ ID NO: 985)5′-GCAGUGUUUUCACCUCAUAUGCUat-3′ (SEQ ID NO: 218)3′-UUCGUCACAAAAGUGGAGUAUACGAUA-5′ (SEQ ID NO: 602) TTR-681 Target:5′-AAGCAGTGTTTTCACCTCATATGCTAT-3′ (SEQ ID NO: 986)5′-CAGUGUUUUCACCUCAUAUGCUAtg-3′ (SEQ ID NO: 219)3′-UCGUCACAAAAGUGGAGUAUACGAUAC-5′ (SEQ ID NO: 603) TTR-682 Target:5′-AGCAGTGTTTTCACCTCATATGCTATG-3′ (SEQ ID NO: 987)5′-AGUGUUUUCACCUCAUAUGCUAUgt-3′ (SEQ ID NO: 220)3′-CGUCACAAAAGUGGAGUAUACGAUACA-5′ (SEQ ID NO: 604) TTR-683 Target:5′-GCAGTGTTTTCACCTCATATGCTATGT-3′ (SEQ ID NO: 988)5′-GUGUUUUCACCUCAUAUGCUAUGtt-3′ (SEQ ID NO: 221)3′-GUCACAAAAGUGGAGUAUACGAUACAA-5′ (SEQ ID NO: 605) TTR-684 Target:5′-CAGTGTTTTCACCTCATATGCTATGTT-3′ (SEQ ID NO: 989)5′-UGUUUUCACCUCAUAUGCUAUGUta-3′ (SEQ ID NO: 222)3′-UCACAAAAGUGGAGUAUACGAUACAAU-5′ (SEQ ID NO: 606) TTR-685 Target:5′-AGTGTTTTCACCTCATATGCTATGTTA-3′ (SEQ ID NO: 990)5′-GUUUUCACCUCAUAUGCUAUGUUag-3′ (SEQ ID NO: 223)3′-CACAAAAGUGGAGUAUACGAUACAAUC-5′ (SEQ ID NO: 607) TTR-686 Target:5′-GTGTTTTCACCTCATATGCTATGTTAG-3′ (SEQ ID NO: 991)5′-UUUUCACCUCAUAUGCUAUGUUAga-3′ (SEQ ID NO: 224)3′-ACAAAAGUGGAGUAUACGAUACAAUCU-5′ (SEQ ID NO: 608) TTR-687 Target:5′-TGTTTTCACCTCATATGCTATGTTAGA-3′ (SEQ ID NO: 992)5′-UUUCACCUCAUAUGCUAUGUUAGaa-3′ (SEQ ID NO: 225)3′-CAAAAGUGGAGUAUACGAUACAAUCUU-5′ (SEQ ID NO: 609) TTR-688 Target:5′-GTTTTCACCTCATATGCTATGTTAGAA-3′ (SEQ ID NO: 993)5′-UUCACCUCAUAUGCUAUGUUAGAag-3′ (SEQ ID NO: 226)3′-AAAAGUGGAGUAUACGAUACAAUCUUC-5′ (SEQ ID NO: 610) TTR-689 Target:5′-TTTTCACCTCATATGCTATGTTAGAAG-3′ (SEQ ID NO: 994)5′-UCACCUCAUAUGCUAUGUUAGAAgt-3′ (SEQ ID NO: 227)3′-AAAGUGGAGUAUACGAUACAAUCUUCA-5′ (SEQ ID NO: 611) TTR-690 Target:5′-TTTCACCTCATATGCTATGTTAGAAGT-3′ (SEQ ID NO: 995)5′-CACCUCAUAUGCUAUGUUAGAAGtc-3′ (SEQ ID NO: 228)3′-AAGUGGAGUAUACGAUACAAUCUUCAG-5′ (SEQ ID NO: 612) TTR-691 Target:5′-TTCACCTCATATGCTATGTTAGAAGTC-3′ (SEQ ID NO: 996)5′-ACCUCAUAUGCUAUGUUAGAAGUcc-3′ (SEQ ID NO: 229)3′-AGUGGAGUAUACGAUACAAUCUUCAGG-5′ (SEQ ID NO: 613) TTR-692 Target:5′-TCACCTCATATGCTATGTTAGAAGTCC-3′ (SEQ ID NO: 997)5′-CCUCAUAUGCUAUGUUAGAAGUCca-3′ (SEQ ID NO: 230)3′-GUGGAGUAUACGAUACAAUCUUCAGGU-5′ (SEQ ID NO: 614) TTR-693 Target:5′-CACCTCATATGCTATGTTAGAAGTCCA-3′ (SEQ ID NO: 998)5′-CUCAUAUGCUAUGUUAGAAGUCCag-3′ (SEQ ID NO: 231)3′-UGGAGUAUACGAUACAAUCUUCAGGUC-5′ (SEQ ID NO: 615) TTR-694 Target:5′-ACCTCATATGCTATGTTAGAAGTCCAG-3′ (SEQ ID NO: 999)5′-UCAUAUGCUAUGUUAGAAGUCCAgg-3′ (SEQ ID NO: 232)3′-GGAGUAUACGAUACAAUCUUCAGGUCC-5′ (SEQ ID NO: 616) TTR-695 Target:5′-CCTCATATGCTATGTTAGAAGTCCAGG-3′ (SEQ ID NO: 1000)5′-CAUAUGCUAUGUUAGAAGUCCAGgc-3′ (SEQ ID NO: 233)3′-GAGUAUACGAUACAAUCUUCAGGUCCG-5′ (SEQ ID NO: 617) TTR-696 Target:5′-CTCATATGCTATGTTAGAAGTCCAGGC-3′ (SEQ ID NO: 1001)5′-AUAUGCUAUGUUAGAAGUCCAGGca-3′ (SEQ ID NO: 234)3′-AGUAUACGAUACAAUCUUCAGGUCCGU-5′ (SEQ ID NO: 618) TTR-697 Target:5′-TCATATGCTATGTTAGAAGTCCAGGCA-3′ (SEQ ID NO: 1002)5′-UAUGCUAUGUUAGAAGUCCAGGCag-3′ (SEQ ID NO: 235)3′-GUAUACGAUACAAUCUUCAGGUCCGUC-5′ (SEQ ID NO: 619) TTR-698 Target:5′-CATATGCTATGTTAGAAGTCCAGGCAG-3′ (SEQ ID NO: 1003)5′-AUGCUAUGUUAGAAGUCCAGGCAga-3′ (SEQ ID NO: 236)3′-UAUACGAUACAAUCUUCAGGUCCGUCU-5′ (SEQ ID NO: 620) TTR-699 Target:5′-ATATGCTATGTTAGAAGTCCAGGCAGA-3′ (SEQ ID NO: 1004)5′-CUAUGUUAGAAGUCCAGGCAGAGac-3′ (SEQ ID NO: 237)3′-ACGAUACAAUCUUCAGGUCCGUCUCUG-5′ (SEQ ID NO: 621) TTR-702 Target:5′-TGCTATGTTAGAAGTCCAGGCAGAGAC-3′ (SEQ ID NO: 1005)5′-AUGUUAGAAGUCCAGGCAGAGACaa-3′ (SEQ ID NO: 238)3′-GAUACAAUCUUCAGGUCCGUCUCUGUU-5′ (SEQ ID NO: 622) TTR-704 Target:5′-CTATGTTAGAAGTCCAGGCAGAGACAA-3′ (SEQ ID NO: 1006)5′-UGUUAGAAGUCCAGGCAGAGACAat-3′ (SEQ ID NO: 239)3′-AUACAAUCUUCAGGUCCGUCUCUGUUA-5′ (SEQ ID NO: 623) TTR-705 Target:5′-TATGTTAGAAGTCCAGGCAGAGACAAT-3′ (SEQ ID NO: 1007)5′-GUUAGAAGUCCAGGCAGAGACAAta-3′ (SEQ ID NO: 240)3′-UACAAUCUUCAGGUCCGUCUCUGUUAU-5′ (SEQ ID NO: 624) TTR-706 Target:5′-ATGTTAGAAGTCCAGGCAGAGACAATA-3′ (SEQ ID NO: 1008)5′-UUAGAAGUCCAGGCAGAGACAAUaa-3′ (SEQ ID NO: 241)3′-ACAAUCUUCAGGUCCGUCUCUGUUAUU-5′ (SEQ ID NO: 625) TTR-707 Target:5′-TGTTAGAAGTCCAGGCAGAGACAATAA-3′ (SEQ ID NO: 1009)5′-UAGAAGUCCAGGCAGAGACAAUAaa-3′ (SEQ ID NO: 242)3′-CAAUCUUCAGGUCCGUCUCUGUUAUUU-5′ (SEQ ID NO: 626) TTR-708 Target:5′-GTTAGAAGTCCAGGCAGAGACAATAAA-3′ (SEQ ID NO: 1010)5′-AGAAGUCCAGGCAGAGACAAUAAaa-3′ (SEQ ID NO: 243)3′-AAUCUUCAGGUCCGUCUCUGUUAUUUU-5′ (SEQ ID NO: 627) TTR-709 Target:5′-TTAGAAGTCCAGGCAGAGACAATAAAA-3′ (SEQ ID NO: 1011)5′-GAAGUCCAGGCAGAGACAAUAAAac-3′ (SEQ ID NO: 244)3′-AUCUUCAGGUCCGUCUCUGUUAUUUUG-5′ (SEQ ID NO: 628) TTR-710 Target:5′-TAGAAGTCCAGGCAGAGACAATAAAAC-3′ (SEQ ID NO: 1012)5′-AAGUCCAGGCAGAGACAAUAAAAca-3′ (SEQ ID NO: 245)3′-UCUUCAGGUCCGUCUCUGUUAUUUUGU-5′ (SEQ ID NO: 629) TTR-711 Target:5′-AGAAGTCCAGGCAGAGACAATAAAACA-3′ (SEQ ID NO: 1013)5′-AGUCCAGGCAGAGACAAUAAAACat-3′ (SEQ ID NO: 246)3′-CUUCAGGUCCGUCUCUGUUAUUUUGUA-5′ (SEQ ID NO: 630) TTR-712 Target:5′-GAAGTCCAGGCAGAGACAATAAAACAT-3′ (SEQ ID NO: 1014)5′-GUCCAGGCAGAGACAAUAAAACAtt-3′ (SEQ ID NO: 247)3′-UUCAGGUCCGUCUCUGUUAUUUUGUAA-5′ (SEQ ID NO: 631) TTR-713 Target:5′-AAGTCCAGGCAGAGACAATAAAACATT-3′ (SEQ ID NO: 1015)5′-UCCAGGCAGAGACAAUAAAACAUtc-3′ (SEQ ID NO: 248)3′-UCAGGUCCGUCUCUGUUAUUUUGUAAG-5′ (SEQ ID NO: 632) TTR-714 Target:5′-AGTCCAGGCAGAGACAATAAAACATTC-3′ (SEQ ID NO: 1016)5′-CAGGCAGAGACAAUAAAACAUUCct-3′ (SEQ ID NO: 249)3′-AGGUCCGUCUCUGUUAUUUUGUAAGGA-5′ (SEQ ID NO: 633) TTR-716 Target:5′-TCCAGGCAGAGACAATAAAACATTCCT-3′ (SEQ ID NO: 1017)5′-AGGCAGAGACAAUAAAACAUUCCtg-3′ (SEQ ID NO: 250)3′-GGUCCGUCUCUGUUAUUUUGUAAGGAC-5′ (SEQ ID NO: 634) TTR-717 Target:5′-CCAGGCAGAGACAATAAAACATTCCTG-3′ (SEQ ID NO: 1018)5′-GGCAGAGACAAUAAAACAUUCCUgt-3′ (SEQ ID NO: 251)3′-GUCCGUCUCUGUUAUUUUGUAAGGACA-5′ (SEQ ID NO: 635) TTR-718 Target:5′-CAGGCAGAGACAATAAAACATTCCTGT-3′ (SEQ ID NO: 1019)5′-GCAGAGACAAUAAAACAUUCCUGtg-3′ (SEQ ID NO: 252)3′-UCCGUCUCUGUUAUUUUGUAAGGACAC-5′ (SEQ ID NO: 636) TTR-719 Target:5′-AGGCAGAGACAATAAAACATTCCTGTG-3′ (SEQ ID NO: 1020)5′-CAGAGACAAUAAAACAUUCCUGUga-3′ (SEQ ID NO: 253)3′-CCGUCUCUGUUAUUUUGUAAGGACACU-5′ (SEQ ID NO: 637) TTR-720 Target:5′-GGCAGAGACAATAAAACATTCCTGTGA-3′ (SEQ ID NO: 1021)5′-AGAGACAAUAAAACAUUCCUGUGaa-3′ (SEQ ID NO: 254)3′-CGUCUCUGUUAUUUUGUAAGGACACUU-5′ (SEQ ID NO: 638) TTR-721 Target:5′-GCAGAGACAATAAAACATTCCTGTGAA-3′ (SEQ ID NO: 1022)5′-GAGACAAUAAAACAUUCCUGUGAaa-3′ (SEQ ID NO: 255)3′-GUCUCUGUUAUUUUGUAAGGACACUUU-5′ (SEQ ID NO: 639) TTR-722 Target:5′-CAGAGACAATAAAACATTCCTGTGAAA-3′ (SEQ ID NO: 1023)5′-AGACAAUAAAACAUUCCUGUGAAag-3′ (SEQ ID NO: 256)3′-UCUCUGUUAUUUUGUAAGGACACUUUC-5′ (SEQ ID NO: 640) TTR-723 Target:5′-AGAGACAATAAAACATTCCTGTGAAAG-3′ (SEQ ID NO: 1024)5′-GACAAUAAAACAUUCCUGUGAAAgg-3′ (SEQ ID NO: 257)3′-CUCUGUUAUUUUGUAAGGACACUUUCC-5′ (SEQ ID NO: 641) TTR-724 Target:5′-GAGACAATAAAACATTCCTGTGAAAGG-3′ (SEQ ID NO: 1025)5′-ACAAUAAAACAUUCCUGUGAAAGgc-3′ (SEQ ID NO: 258)3′-UCUGUUAUUUUGUAAGGACACUUUCCG-5′ (SEQ ID NO: 642) TTR-725 Target:5′-AGACAATAAAACATTCCTGTGAAAGGC-3′ (SEQ ID NO: 1026)5′-CAAUAAAACAUUCCUGUGAAAGGca-3′ (SEQ ID NO: 259)3′-CUGUUAUUUUGUAAGGACACUUUCCGU-5′ (SEQ ID NO: 643) TTR-726 Target:5′-GACAATAAAACATTCCTGTGAAAGGCA-3′ (SEQ ID NO: 1027)5′-AAUAAAACAUUCCUGUGAAAGGCac-3′ (SEQ ID NO: 260)3′-UGUUAUUUUGUAAGGACACUUUCCGUG-5′ (SEQ ID NO: 644) TTR-727 Target:5′-ACAATAAAACATTCCTGTGAAAGGCAC-3′ (SEQ ID NO: 1028)5′-AUAAAACAUUCCUGUGAAAGGCAct-3′ (SEQ ID NO: 261)3′-GUUAUUUUGUAAGGACACUUUCCGUGA-5′ (SEQ ID NO: 645) TTR-728 Target:5′-CAATAAAACATTCCTGTGAAAGGCACT-3′ (SEQ ID NO: 1029)5′-AAACAUUCCUGUGAAAGGCACUUtt-3′ (SEQ ID NO: 262)3′-AUUUUGUAAGGACACUUUCCGUGAAAA-5′ (SEQ ID NO: 646) TTR-731 Target:5′-TAAAACATTCCTGTGAAAGGCACTTTT-3′ (SEQ ID NO: 1030)5′-AACAUUCCUGUGAAAGGCACUUUtc-3′ (SEQ ID NO: 263)3′-UUUUGUAAGGACACUUUCCGUGAAAAG-5′ (SEQ ID NO: 647) TTR-732 Target:5′-AAAACATTCCTGTGAAAGGCACTTTTC-3′ (SEQ ID NO: 1031)5′-ACAUUCCUGUGAAAGGCACUUUUca-3′ (SEQ ID NO: 264)3′-UUUGUAAGGACACUUUCCGUGAAAAGU-5′ (SEQ ID NO: 648) TTR-733 Target:5′-AAACATTCCTGTGAAAGGCACTTTTCA-3′ (SEQ ID NO: 1032)5′-CAUUCCUGUGAAAGGCACUUUUCat-3′ (SEQ ID NO: 265)3′-UUGUAAGGACACUUUCCGUGAAAAGUA-5′ (SEQ ID NO: 649) TTR-734 Target:5′-AACATTCCTGTGAAAGGCACTTTTCAT-3′ (SEQ ID NO: 1033)5′-AUUCCUGUGAAAGGCACUUUUCAtt-3′ (SEQ ID NO: 266)3′-UGUAAGGACACUUUCCGUGAAAAGUAA-5′ (SEQ ID NO: 650) TTR-735 Target:5′-ACATTCCTGTGAAAGGCACTTTTCATT-3′ (SEQ ID NO: 1034)5′-UUCCUGUGAAAGGCACUUUUCAUtc-3′ (SEQ ID NO: 267)3′-GUAAGGACACUUUCCGUGAAAAGUAAG-5′ (SEQ ID NO: 651) TTR-736 Target:5′-CATTCCTGTGAAAGGCACTTTTCATTC-3′ (SEQ ID NO: 1035)5′-CCUGUGAAAGGCACUUUUCAUUCca-3′ (SEQ ID NO: 268)3′-AAGGACACUUUCCGUGAAAAGUAAGGU-5′ (SEQ ID NO: 652) TTR-738 Target:5′-TTCCTGTGAAAGGCACTTTTCATTCCA-3′ (SEQ ID NO: 1036)5′-CUGUGAAAGGCACUUUUCAUUCCac-3′ (SEQ ID NO: 269)3′-AGGACACUUUCCGUGAAAAGUAAGGUG-5′ (SEQ ID NO: 653) TTR-739 Target:5′-TCCTGTGAAAGGCACTTTTCATTCCAC-3′ (SEQ ID NO: 1037)5′-UGUGAAAGGCACUUUUCAUUCCAct-3′ (SEQ ID NO: 270)3′-GGACACUUUCCGUGAAAAGUAAGGUGA-5′ (SEQ ID NO: 654) TTR-740 Target:5′-CCTGTGAAAGGCACTTTTCATTCCACT-3′ (SEQ ID NO: 1038)5′-GUGAAAGGCACUUUUCAUUCCACtt-3′ (SEQ ID NO: 271)3′-GACACUUUCCGUGAAAAGUAAGGUGAA-5′ (SEQ ID NO: 655) TTR-741 Target:5′-CTGTGAAAGGCACTTTTCATTCCACTT-3′ (SEQ ID NO: 1039)5′-UGAAAGGCACUUUUCAUUCCACUtt-3′ (SEQ ID NO: 272)3′-ACACUUUCCGUGAAAAGUAAGGUGAAA-5′ (SEQ ID NO: 656) TTR-742 Target:5′-TGTGAAAGGCACTTTTCATTCCACTTT-3′ (SEQ ID NO: 1040)5′-GAAAGGCACUUUUCAUUCCACUUta-3′ (SEQ ID NO: 273)3′-CACUUUCCGUGAAAAGUAAGGUGAAAU-5′ (SEQ ID NO: 657) TTR-743 Target:5′-GTGAAAGGCACTTTTCATTCCACTTTA-3′ (SEQ ID NO: 1041)5′-AAAGGCACUUUUCAUUCCACUUUaa-3′ (SEQ ID NO: 274)3′-ACUUUCCGUGAAAAGUAAGGUGAAAUU-5′ (SEQ ID NO: 658) TTR-744 Target:5′-TGAAAGGCACTTTTCATTCCACTTTAA-3′ (SEQ ID NO: 1042)5′-AAGGCACUUUUCAUUCCACUUUAac-3′ (SEQ ID NO: 275)3′-CUUUCCGUGAAAAGUAAGGUGAAAUUG-5′ (SEQ ID NO: 659) TTR-745 Target:5′-GAAAGGCACTTTTCATTCCACTTTAAC-3′ (SEQ ID NO: 1043)5′-AGGCACUUUUCAUUCCACUUUAAct-3′ (SEQ ID NO: 276)3′-UUUCCGUGAAAAGUAAGGUGAAAUUGA-5′ (SEQ ID NO: 660) TTR-746 Target:5′-AAAGGCACTTTTCATTCCACTTTAACT-3′ (SEQ ID NO: 1044)5′-GGCACUUUUCAUUCCACUUUAACtt-3′ (SEQ ID NO: 277)3′-UUCCGUGAAAAGUAAGGUGAAAUUGAA-5′ (SEQ ID NO: 661) TTR-747 Target:5′-AAGGCACTTTTCATTCCACTTTAACTT-3′ (SEQ ID NO: 1045)5′-GCACUUUUCAUUCCACUUUAACUtg-3′ (SEQ ID NO: 278)3′-UCCGUGAAAAGUAAGGUGAAAUUGAAC-5′ (SEQ ID NO: 662) TTR-748 Target:5′-AGGCACTTTTCATTCCACTTTAACTTG-3′ (SEQ ID NO: 1046)5′-CACUUUUCAUUCCACUUUAACUUga-3′ (SEQ ID NO: 279)3′-CCGUGAAAAGUAAGGUGAAAUUGAACU-5′ (SEQ ID NO: 663) TTR-749 Target:5′-GGCACTTTTCATTCCACTTTAACTTGA-3′ (SEQ ID NO: 1047)5′-ACUUUUCAUUCCACUUUAACUUGat-3′ (SEQ ID NO: 280)3′-CGUGAAAAGUAAGGUGAAAUUGAACUA-5′ (SEQ ID NO: 664) TTR-750 Target:5′-GCACTTTTCATTCCACTTTAACTTGAT-3′ (SEQ ID NO: 1048)5′-CUUUUCAUUCCACUUUAACUUGAtt-3′ (SEQ ID NO: 281)3′-GUGAAAAGUAAGGUGAAAUUGAACUAA-5′ (SEQ ID NO: 665) TTR-751 Target:5′-CACTTTTCATTCCACTTTAACTTGATT-3′ (SEQ ID NO: 1049)5′-UUUUCAUUCCACUUUAACUUGAUtt-3′ (SEQ ID NO: 282)3′-UGAAAAGUAAGGUGAAAUUGAACUAAA-5′ (SEQ ID NO: 666) TTR-752 Target:5′-ACTTTTCATTCCACTTTAACTTGATTT-3′ (SEQ ID NO: 1050)5′-UUUCAUUCCACUUUAACUUGAUUtt-3′ (SEQ ID NO: 283)3′-GAAAAGUAAGGUGAAAUUGAACUAAAA-5′ (SEQ ID NO: 667) TTR-753 Target:5′-CTTTTCATTCCACTTTAACTTGATTTT-3′ (SEQ ID NO: 1051)5′-UUCAUUCCACUUUAACUUGAUUUtt-3′ (SEQ ID NO: 284)3′-AAAAGUAAGGUGAAAUUGAACUAAAAA-5′ (SEQ ID NO: 668) TTR-754 Target:5′-TTTTCATTCCACTTTAACTTGATTTTT-3′ (SEQ ID NO: 1052)5′-UCAUUCCACUUUAACUUGAUUUUtt-3′ (SEQ ID NO: 285)3′-AAAGUAAGGUGAAAUUGAACUAAAAAA-5′ (SEQ ID NO: 669) TTR-755 Target:5′-TTTCATTCCACTTTAACTTGATTTTTT-3′ (SEQ ID NO: 1053)5′-CAUUCCACUUUAACUUGAUUUUUta-3′ (SEQ ID NO: 286)3′-AAGUAAGGUGAAAUUGAACUAAAAAAU-5′ (SEQ ID NO: 670) TTR-756 Target:5′-TTCATTCCACTTTAACTTGATTTTTTA-3′ (SEQ ID NO: 1054)5′-AUUCCACUUUAACUUGAUUUUUUaa-3′ (SEQ ID NO: 287)3′-AGUAAGGUGAAAUUGAACUAAAAAAUU-5′ (SEQ ID NO: 671) TTR-757 Target:5′-TCATTCCACTTTAACTTGATTTTTTAA-3′ (SEQ ID NO: 1055)5′-UUCCACUUUAACUUGAUUUUUUAaa-3′ (SEQ ID NO: 288)3′-GUAAGGUGAAAUUGAACUAAAAAAUUU-5′ (SEQ ID NO: 672) TTR-758 Target:5′-CATTCCACTTTAACTTGATTTTTTAAA-3′ (SEQ ID NO: 1056)5′-UCCACUUUAACUUGAUUUUUUAAat-3′ (SEQ ID NO: 289)3′-UAAGGUGAAAUUGAACUAAAAAAUUUA-5′ (SEQ ID NO: 673) TTR-759 Target:5′-ATTCCACTTTAACTTGATTTTTTAAAT-3′ (SEQ ID NO: 1057)5′-CCACUUUAACUUGAUUUUUUAAAtt-3′ (SEQ ID NO: 290)3′-AAGGUGAAAUUGAACUAAAAAAUUUAA-5′ (SEQ ID NO: 674) TTR-760 Target:5′-TTCCACTTTAACTTGATTTTTTAAATT-3′ (SEQ ID NO: 1058)5′-CACUUUAACUUGAUUUUUUAAAUtc-3′ (SEQ ID NO: 291)3′-AGGUGAAAUUGAACUAAAAAAUUUAAG-5′ (SEQ ID NO: 675) TTR-761 Target:5′-TCCACTTTAACTTGATTTTTTAAATTC-3′ (SEQ ID NO: 1059)5′-ACUUUAACUUGAUUUUUUAAAUUcc-3′ (SEQ ID NO: 292)3′-GGUGAAAUUGAACUAAAAAAUUUAAGG-5′ (SEQ ID NO: 676) TTR-762 Target:5′-CCACTTTAACTTGATTTTTTAAATTCC-3′ (SEQ ID NO: 1060)5′-CUUUAACUUGAUUUUUUAAAUUCcc-3′ (SEQ ID NO: 293)3′-GUGAAAUUGAACUAAAAAAUUUAAGGG-5′ (SEQ ID NO: 677) TTR-763 Target:5′-CACTTTAACTTGATTTTTTAAATTCCC-3′ (SEQ ID NO: 1061)5′-UUUAACUUGAUUUUUUAAAUUCCct-3′ (SEQ ID NO: 294)3′-UGAAAUUGAACUAAAAAAUUUAAGGGA-5′ (SEQ ID NO: 678) TTR-764 Target:5′-ACTTTAACTTGATTTTTTAAATTCCCT-3′ (SEQ ID NO: 1062)5′-UUAACUUGAUUUUUUAAAUUCCCtt-3′ (SEQ ID NO: 295)3′-GAAAUUGAACUAAAAAAUUUAAGGGAA-5′ (SEQ ID NO: 679) TTR-765 Target:5′-CTTTAACTTGATTTTTTAAATTCCCTT-3′ (SEQ ID NO: 1063)5′-UAACUUGAUUUUUUAAAUUCCCUta-3′ (SEQ ID NO: 296)3′-AAAUUGAACUAAAAAAUUUAAGGGAAU-5′ (SEQ ID NO: 680) TTR-766 Target:5′-TTTAACTTGATTTTTTAAATTCCCTTA-3′ (SEQ ID NO: 1064)5′-AACUUGAUUUUUUAAAUUCCCUUat-3′ (SEQ ID NO: 297)3′-AAUUGAACUAAAAAAUUUAAGGGAAUA-5′ (SEQ ID NO: 681) TTR-767 Target:5′-TTAACTTGATTTTTTAAATTCCCTTAT-3′ (SEQ ID NO: 1065)5′-ACUUGAUUUUUUAAAUUCCCUUAtt-3′ (SEQ ID NO: 298)3′-AUUGAACUAAAAAAUUUAAGGGAAUAA-5′ (SEQ ID NO: 682) TTR-768 Target:5′-TAACTTGATTTTTTAAATTCCCTTATT-3′ (SEQ ID NO: 1066)5′-CUUGAUUUUUUAAAUUCCCUUAUtg-3′ (SEQ ID NO: 299)3′-UUGAACUAAAAAAUUUAAGGGAAUAAC-5′ (SEQ ID NO: 683) TTR-769 Target:5′-AACTTGATTTTTTAAATTCCCTTATTG-3′ (SEQ ID NO: 1067)5′-UUGAUUUUUUAAAUUCCCUUAUUgt-3′ (SEQ ID NO: 300)3′-UGAACUAAAAAAUUUAAGGGAAUAACA-5′ (SEQ ID NO: 684) TTR-770 Target:5′-ACTTGATTTTTTAAATTCCCTTATTGT-3′ (SEQ ID NO: 1068)5′-UGAUUUUUUAAAUUCCCUUAUUGtc-3′ (SEQ ID NO: 301)3′-GAACUAAAAAAUUUAAGGGAAUAACAG-5′ (SEQ ID NO: 685) TTR-771 Target:5′-CTTGATTTTTTAAATTCCCTTATTGTC-3′ (SEQ ID NO: 1069)5′-GAUUUUUUAAAUUCCCUUAUUGUcc-3′ (SEQ ID NO: 302)3′-AACUAAAAAAUUUAAGGGAAUAACAGG-5′ (SEQ ID NO: 686) TTR-772 Target:5′-TTGATTTTTTAAATTCCCTTATTGTCC-3′ (SEQ ID NO: 1070)5′-AUUUUUUAAAUUCCCUUAUUGUCcc-3′ (SEQ ID NO: 303)3′-ACUAAAAAAUUUAAGGGAAUAACAGGG-5′ (SEQ ID NO: 687) TTR-773 Target:5′-TGATTTTTTAAATTCCCTTATTGTCCC-3′ (SEQ ID NO: 1071)5′-UUUUUAAAUUCCCUUAUUGUCCCtt-3′ (SEQ ID NO: 304)3′-UAAAAAAUUUAAGGGAAUAACAGGGAA-5′ (SEQ ID NO: 688) TTR-775 Target:5′-ATTTTTTAAATTCCCTTATTGTCCCTT-3′ (SEQ ID NO: 1072)5′-AAAUUCCCUUAUUGUCCCUUCCAaa-3′ (SEQ ID NO: 305)3′-AAUUUAAGGGAAUAACAGGGAAGGUUU-5′ (SEQ ID NO: 689) TTR-780 Target:5′-TTAAATTCCCTTATTGTCCCTTCCAAA-3′ (SEQ ID NO: 1073)5′-AAUUCCCUUAUUGUCCCUUCCAAaa-3′ (SEQ ID NO: 306)3′-AUUUAAGGGAAUAACAGGGAAGGUUUU-5′ (SEQ ID NO: 690) TTR-781 Target:5′-TAAATTCCCTTATTGTCCCTTCCAAAA-3′ (SEQ ID NO: 1074)5′-UCCCUUAUUGUCCCUUCCAAAAAaa-3′ (SEQ ID NO: 307)3′-UAAGGGAAUAACAGGGAAGGUUUUUUU-5′ (SEQ ID NO: 691) TTR-784 Target:5′-ATTCCCTTATTGTCCCTTCCAAAAAAA-3′ (SEQ ID NO: 1075)5′-AAAAAGAGAAUCAAAAUUUUACAaa-3′ (SEQ ID NO: 308)3′-UUUUUUUCUCUUAGUUUUAAAAUGUUU-5′ (SEQ ID NO: 692) TTR-805 Target:5′-AAAAAAAGAGAATCAAAATTTTACAAA-3′ (SEQ ID NO: 1076)5′-AAAAGAGAAUCAAAAUUUUACAAag-3′ (SEQ ID NO: 309)3′-UUUUUUCUCUUAGUUUUAAAAUGUUUC-5′ (SEQ ID NO: 693) TTR-806 Target:5′-AAAAAAGAGAATCAAAATTTTACAAAG-3′ (SEQ ID NO: 1077)5′-AAAGAGAAUCAAAAUUUUACAAAga-3′ (SEQ ID NO: 310)3′-UUUUUCUCUUAGUUUUAAAAUGUUUCU-5′ (SEQ ID NO: 694) TTR-807 Target:5′-AAAAAGAGAATCAAAATTTTACAAAGA-3′ (SEQ ID NO: 1078)5′-AAGAGAAUCAAAAUUUUACAAAGaa-3′ (SEQ ID NO: 311)3′-UUUUCUCUUAGUUUUAAAAUGUUUCUU-5′ (SEQ ID NO: 695) TTR-808 Target:5′-AAAAGAGAATCAAAATTTTACAAAGAA-3′ (SEQ ID NO: 1079)5′-AGAGAAUCAAAAUUUUACAAAGAat-3′ (SEQ ID NO: 312)3′-UUUCUCUUAGUUUUAAAAUGUUUCUUA-5′ (SEQ ID NO: 696) TTR-809 Target:5′-AAAGAGAATCAAAATTTTACAAAGAAT-3′ (SEQ ID NO: 1080)5′-GAGAAUCAAAAUUUUACAAAGAAtc-3′ (SEQ ID NO: 313)3′-UUCUCUUAGUUUUAAAAUGUUUCUUAG-5′ (SEQ ID NO: 697) TTR-810 Target:5′-AAGAGAATCAAAATTTTACAAAGAATC-3′ (SEQ ID NO: 1081)5′-AGAAUCAAAAUUUUACAAAGAAUca-3′ (SEQ ID NO: 314)3′-UCUCUUAGUUUUAAAAUGUUUCUUAGU-5′ (SEQ ID NO: 698) TTR-811 Target:5′-AGAGAATCAAAATTTTACAAAGAATCA-3′ (SEQ ID NO: 1082)5′-GAAUCAAAAUUUUACAAAGAAUCaa-3′ (SEQ ID NO: 315)3′-CUCUUAGUUUUAAAAUGUUUCUUAGUU-5′ (SEQ ID NO: 699) TTR-812 Target:5′-GAGAATCAAAATTTTACAAAGAATCAA-3′ (SEQ ID NO: 1083)5′-AAUCAAAAUUUUACAAAGAAUCAaa-3′ (SEQ ID NO: 316)3′-UCUUAGUUUUAAAAUGUUUCUUAGUUU-5′ (SEQ ID NO: 700) TTR-813 Target:5′-AGAATCAAAATTTTACAAAGAATCAAA-3′ (SEQ ID NO: 1084)5′-AUCAAAAUUUUACAAAGAAUCAAag-3′ (SEQ ID NO: 317)3′-CUUAGUUUUAAAAUGUUUCUUAGUUUC-5′ (SEQ ID NO: 701) TTR-814 Target:5′-GAATCAAAATTTTACAAAGAATCAAAG-3′ (SEQ ID NO: 1085)5′-UCAAAAUUUUACAAAGAAUCAAAgg-3′ (SEQ ID NO: 318)3′-UUAGUUUUAAAAUGUUUCUUAGUUUCC-5′ (SEQ ID NO: 702) TTR-815 Target:5′-AATCAAAATTTTACAAAGAATCAAAGG-3′ (SEQ ID NO: 1086)5′-CAAAAUUUUACAAAGAAUCAAAGga-3′ (SEQ ID NO: 319)3′-UAGUUUUAAAAUGUUUCUUAGUUUCCU-5′ (SEQ ID NO: 703) TTR-816 Target:5′-ATCAAAATTTTACAAAGAATCAAAGGA-3′ (SEQ ID NO: 1087)5′-AAAAUUUUACAAAGAAUCAAAGGaa-3′ (SEQ ID NO: 320)3′-AGUUUUAAAAUGUUUCUUAGUUUCCUU-5′ (SEQ ID NO: 704) TTR-817 Target:5′-TCAAAATTTTACAAAGAATCAAAGGAA-3′ (SEQ ID NO: 1088)5′-AAAUUUUACAAAGAAUCAAAGGAat-3′ (SEQ ID NO: 321)3′-GUUUUAAAAUGUUUCUUAGUUUCCUUA-5′ (SEQ ID NO: 705) TTR-818 Target:5′-CAAAATTTTACAAAGAATCAAAGGAAT-3′ (SEQ ID NO: 1089)5′-AAUUUUACAAAGAAUCAAAGGAAtt-3′ (SEQ ID NO: 322)3′-UUUUAAAAUGUUUCUUAGUUUCCUUAA-5′ (SEQ ID NO: 706) TTR-819 Target:5′-AAAATTTTACAAAGAATCAAAGGAATT-3′ (SEQ ID NO: 1090)5′-UUUUACAAAGAAUCAAAGGAAUUct-3′ (SEQ ID NO: 323)3′-UUAAAAUGUUUCUUAGUUUCCUUAAGA-5′ (SEQ ID NO: 707) TTR-821 Target:5′-AATTTTACAAAGAATCAAAGGAATTCT-3′ (SEQ ID NO: 1091)5′-UUUACAAAGAAUCAAAGGAAUUCta-3′ (SEQ ID NO: 324)3′-UAAAAUGUUUCUUAGUUUCCUUAAGAU-5′ (SEQ ID NO: 708) TTR-822 Target:5′-ATTTTACAAAGAATCAAAGGAATTCTA-3′ (SEQ ID NO: 1092)5′-UUACAAAGAAUCAAAGGAAUUCUag-3′ (SEQ ID NO: 325)3′-AAAAUGUUUCUUAGUUUCCUUAAGAUC-5′ (SEQ ID NO: 709) TTR-823 Target:5′-TTTTACAAAGAATCAAAGGAATTCTAG-3′ (SEQ ID NO: 1093)5′-UACAAAGAAUCAAAGGAAUUCUAga-3′ (SEQ ID NO: 326)3′-AAAUGUUUCUUAGUUUCCUUAAGAUCU-5′ (SEQ ID NO: 710) TTR-824 Target:5′-TTTACAAAGAATCAAAGGAATTCTAGA-3′ (SEQ ID NO: 1094)5′-ACAAAGAAUCAAAGGAAUUCUAGaa-3′ (SEQ ID NO: 327)3′-AAUGUUUCUUAGUUUCCUUAAGAUCUU-5′ (SEQ ID NO: 711) TTR-825 Target:5′-TTACAAAGAATCAAAGGAATTCTAGAA-3′ (SEQ ID NO: 1095)5′-CAAAGAAUCAAAGGAAUUCUAGAaa-3′ (SEQ ID NO: 328)3′-AUGUUUCUUAGUUUCCUUAAGAUCUUU-5′ (SEQ ID NO: 712) TTR-826 Target:5′-TACAAAGAATCAAAGGAATTCTAGAAA-3′ (SEQ ID NO: 1096)5′-AAAGAAUCAAAGGAAUUCUAGAAag-3′ (SEQ ID NO: 329)3′-UGUUUCUUAGUUUCCUUAAGAUCUUUC-5′ (SEQ ID NO: 713) TTR-827 Target:5′-ACAAAGAATCAAAGGAATTCTAGAAAG-3′ (SEQ ID NO: 1097)5′-AAGAAUCAAAGGAAUUCUAGAAAgt-3′ (SEQ ID NO: 330)3′-GUUUCUUAGUUUCCUUAAGAUCUUUCA-5′ (SEQ ID NO: 714) TTR-828 Target:5′-CAAAGAATCAAAGGAATTCTAGAAAGT-3′ (SEQ ID NO: 1098)5′-AGAAUCAAAGGAAUUCUAGAAAGta-3′ (SEQ ID NO: 331)3′-UUUCUUAGUUUCCUUAAGAUCUUUCAU-5′ (SEQ ID NO: 715) TTR-829 Target:5′-AAAGAATCAAAGGAATTCTAGAAAGTA-3′ (SEQ ID NO: 1099)5′-GAAUCAAAGGAAUUCUAGAAAGUat-3′ (SEQ ID NO: 332)3′-UUCUUAGUUUCCUUAAGAUCUUUCAUA-5′ (SEQ ID NO: 716) TTR-830 Target:5′-AAGAATCAAAGGAATTCTAGAAAGTAT-3′ (SEQ ID NO: 1100)5′-AAUCAAAGGAAUUCUAGAAAGUAtc-3′ (SEQ ID NO: 333)3′-UCUUAGUUUCCUUAAGAUCUUUCAUAG-5′ (SEQ ID NO: 717) TTR-831 Target:5′-AGAATCAAAGGAATTCTAGAAAGTATC-3′ (SEQ ID NO: 1101)5′-AUCAAAGGAAUUCUAGAAAGUAUct-3′ (SEQ ID NO: 334)3′-CUUAGUUUCCUUAAGAUCUUUCAUAGA-5′ (SEQ ID NO: 718) TTR-832 Target:5′-GAATCAAAGGAATTCTAGAAAGTATCT-3′ (SEQ ID NO: 1102)5′-UCAAAGGAAUUCUAGAAAGUAUCtg-3′ (SEQ ID NO: 335)3′-UUAGUUUCCUUAAGAUCUUUCAUAGAC-5′ (SEQ ID NO: 719) TTR-833 Target:5′-AATCAAAGGAATTCTAGAAAGTATCTG-3′ (SEQ ID NO: 1103)5′-CAAAGGAAUUCUAGAAAGUAUCUgg-3′ (SEQ ID NO: 336)3′-UAGUUUCCUUAAGAUCUUUCAUAGACC-5′ (SEQ ID NO: 720) TTR-834 Target:5′-ATCAAAGGAATTCTAGAAAGTATCTGG-3′ (SEQ ID NO: 1104)5′-AAAGGAAUUCUAGAAAGUAUCUGgg-3′ (SEQ ID NO: 337)3′-AGUUUCCUUAAGAUCUUUCAUAGACCC-5′ (SEQ ID NO: 721) TTR-835 Target:5′-TCAAAGGAATTCTAGAAAGTATCTGGG-3′ (SEQ ID NO: 1105)5′-AGGAGAGAUCCAAAUUUCCAUUGtc-3′ (SEQ ID NO: 338)3′-GAUCCUCUCUAGGUUUAAAGGUAACAG-5′ (SEQ ID NO: 722) TTR-869 Target:5′-CTAGGAGAGATCCAAATTTCCATTGTC-3′ (SEQ ID NO: 1106)5′-GGAGAGAUCCAAAUUUCCAUUGUct-3′ (SEQ ID NO: 339)3′-AUCCUCUCUAGGUUUAAAGGUAACAGA-5′ (SEQ ID NO: 723) TTR-870 Target:5′-TAGGAGAGATCCAAATTTCCATTGTCT-3′ (SEQ ID NO: 1107)5′-GAGAUCCAAAUUUCCAUUGUCUUgc-3′ (SEQ ID NO: 340)3′-CUCUCUAGGUUUAAAGGUAACAGAACG-5′ (SEQ ID NO: 724) TTR-873 Target:5′-GAGAGATCCAAATTTCCATTGTCTTGC-3′ (SEQ ID NO: 1108)5′-AGAUCCAAAUUUCCAUUGUCUUGca-3′ (SEQ ID NO: 341)3′-UCUCUAGGUUUAAAGGUAACAGAACGU-5′ (SEQ ID NO: 725) TTR-874 Target:5′-AGAGATCCAAATTTCCATTGTCTTGCA-3′ (SEQ ID NO: 1109)5′-GAUCCAAAUUUCCAUUGUCUUGCaa-3′ (SEQ ID NO: 342)3′-CUCUAGGUUUAAAGGUAACAGAACGUU-5′ (SEQ ID NO: 726) TTR-875 Target:5′-GAGATCCAAATTTCCATTGTCTTGCAA-3′ (SEQ ID NO: 1110)5′-AUCCAAAUUUCCAUUGUCUUGCAag-3′ (SEQ ID NO: 343)3′-UCUAGGUUUAAAGGUAACAGAACGUUC-5′ (SEQ ID NO: 727) TTR-876 Target:5′-AGATCCAAATTTCCATTGTCTTGCAAG-3′ (SEQ ID NO: 1111)5′-UCCAAAUUUCCAUUGUCUUGCAAgc-3′ (SEQ ID NO: 344)3′-CUAGGUUUAAAGGUAACAGAACGUUCG-5′ (SEQ ID NO: 728) TTR-877 Target:5′-GATCCAAATTTCCATTGTCTTGCAAGC-3′ (SEQ ID NO: 1112)5′-CCAAAUUUCCAUUGUCUUGCAAGca-3′ (SEQ ID NO: 345)3′-UAGGUUUAAAGGUAACAGAACGUUCGU-5′ (SEQ ID NO: 729) TTR-878 Target:5′-ATCCAAATTTCCATTGTCTTGCAAGCA-3′ (SEQ ID NO: 1113)5′-CAAAUUUCCAUUGUCUUGCAAGCaa-3′ (SEQ ID NO: 346)3′-AGGUUUAAAGGUAACAGAACGUUCGUU-5′ (SEQ ID NO: 730) TTR-879 Target:5′-TCCAAATTTCCATTGTCTTGCAAGCAA-3′ (SEQ ID NO: 1114)5′-AAAUUUCCAUUGUCUUGCAAGCAaa-3′ (SEQ ID NO: 347)3′-GGUUUAAAGGUAACAGAACGUUCGUUU-5′ (SEQ ID NO: 731) TTR-880 Target:5′-CCAAATTTCCATTGTCTTGCAAGCAAA-3′ (SEQ ID NO: 1115)5′-AAUUUCCAUUGUCUUGCAAGCAAag-3′ (SEQ ID NO: 348)3′-GUUUAAAGGUAACAGAACGUUCGUUUC-5′ (SEQ ID NO: 732) TTR-881 Target:5′-CAAATTTCCATTGTCTTGCAAGCAAAG-3′ (SEQ ID NO: 1116)5′-AUUUCCAUUGUCUUGCAAGCAAAgc-3′ (SEQ ID NO: 349)3′-UUUAAAGGUAACAGAACGUUCGUUUCG-5′ (SEQ ID NO: 733) TTR-882 Target:5′-AAATTTCCATTGTCTTGCAAGCAAAGC-3′ (SEQ ID NO: 1117)5′-UUUCCAUUGUCUUGCAAGCAAAGca-3′ (SEQ ID NO: 350)3′-UUAAAGGUAACAGAACGUUCGUUUCGU-5′ (SEQ ID NO: 734) TTR-883 Target:5′-AATTTCCATTGTCTTGCAAGCAAAGCA-3′ (SEQ ID NO: 1118)5′-UUCCAUUGUCUUGCAAGCAAAGCac-3′ (SEQ ID NO: 351)3′-UAAAGGUAACAGAACGUUCGUUUCGUG-5′ (SEQ ID NO: 735) TTR-884 Target:5′-ATTTCCATTGTCTTGCAAGCAAAGCAC-3′ (SEQ ID NO: 1119)5′-UCCAUUGUCUUGCAAGCAAAGCAcg-3′ (SEQ ID NO: 352)3′-AAAGGUAACAGAACGUUCGUUUCGUGC-5′ (SEQ ID NO: 736) TTR-885 Target:5′-TTTCCATTGTCTTGCAAGCAAAGCACG-3′ (SEQ ID NO: 1120)5′-CCAUUGUCUUGCAAGCAAAGCACgt-3′ (SEQ ID NO: 353)3′-AAGGUAACAGAACGUUCGUUUCGUGCA-5′ (SEQ ID NO: 737) TTR-886 Target:5′-TTCCATTGTCTTGCAAGCAAAGCACGT-3′ (SEQ ID NO: 1121)5′-CAUUGUCUUGCAAGCAAAGCACGta-3′ (SEQ ID NO: 354)3′-AGGUAACAGAACGUUCGUUUCGUGCAU-5′ (SEQ ID NO: 738) TTR-887 Target:5′-TCCATTGTCTTGCAAGCAAAGCACGTA-3′ (SEQ ID NO: 1122)5′-AUUGUCUUGCAAGCAAAGCACGUat-3′ (SEQ ID NO: 355)3′-GGUAACAGAACGUUCGUUUCGUGCAUA-5′ (SEQ ID NO: 739) TTR-888 Target:5′-CCATTGTCTTGCAAGCAAAGCACGTAT-3′ (SEQ ID NO: 1123)5′-UUGUCUUGCAAGCAAAGCACGUAtt-3′ (SEQ ID NO: 356)3′-GUAACAGAACGUUCGUUUCGUGCAUAA-5′ (SEQ ID NO: 740) TTR-889 Target:5′-CATTGTCTTGCAAGCAAAGCACGTATT-3′ (SEQ ID NO: 1124)5′-UGUCUUGCAAGCAAAGCACGUAUta-3′ (SEQ ID NO: 357)3′-UAACAGAACGUUCGUUUCGUGCAUAAU-5′ (SEQ ID NO: 741) TTR-890 Target:5′-ATTGTCTTGCAAGCAAAGCACGTATTA-3′ (SEQ ID NO: 1125)5′-GUCUUGCAAGCAAAGCACGUAUUaa-3′ (SEQ ID NO: 358)3′-AACAGAACGUUCGUUUCGUGCAUAAUU-5′ (SEQ ID NO: 742) TTR-891 Target:5′-TTGTCTTGCAAGCAAAGCACGTATTAA-3′ (SEQ ID NO: 1126)5′-UCUUGCAAGCAAAGCACGUAUUAaa-3′ (SEQ ID NO: 359)3′-ACAGAACGUUCGUUUCGUGCAUAAUUU-5′ (SEQ ID NO: 743) TTR-892 Target:5′-TGTCTTGCAAGCAAAGCACGTATTAAA-3′ (SEQ ID NO: 1127)5′-CUUGCAAGCAAAGCACGUAUUAAat-3′ (SEQ ID NO: 360)3′-CAGAACGUUCGUUUCGUGCAUAAUUUA-5′ (SEQ ID NO: 744) TTR-893 Target:5′-GTCTTGCAAGCAAAGCACGTATTAAAT-3′ (SEQ ID NO: 1128)5′-UUGCAAGCAAAGCACGUAUUAAAta-3′ (SEQ ID NO: 361)3′-AGAACGUUCGUUUCGUGCAUAAUUUAU-5′ (SEQ ID NO: 745) TTR-894 Target:5′-TCTTGCAAGCAAAGCACGTATTAAATA-3′ (SEQ ID NO: 1129)5′-UGCAAGCAAAGCACGUAUUAAAUat-3′ (SEQ ID NO: 362)3′-GAACGUUCGUUUCGUGCAUAAUUUAUA-5′ (SEQ ID NO: 746) TTR-895 Target:5′-CTTGCAAGCAAAGCACGTATTAAATAT-3′ (SEQ ID NO: 1130)5′-GCAAGCAAAGCACGUAUUAAAUAtg-3′ (SEQ ID NO: 363)3′-AACGUUCGUUUCGUGCAUAAUUUAUAC-5′ (SEQ ID NO: 747) TTR-896 Target:5′-TTGCAAGCAAAGCACGTATTAAATATG-3′ (SEQ ID NO: 1131)5′-CAAGCAAAGCACGUAUUAAAUAUga-3′ (SEQ ID NO: 364)3′-ACGUUCGUUUCGUGCAUAAUUUAUACU-5′ (SEQ ID NO: 748) TTR-897 Target:5′-TGCAAGCAAAGCACGTATTAAATATGA-3′ (SEQ ID NO: 1132)5′-AAGCAAAGCACGUAUUAAAUAUGat-3′ (SEQ ID NO: 365)3′-CGUUCGUUUCGUGCAUAAUUUAUACUA-5′ (SEQ ID NO: 749) TTR-898 Target:5′-GCAAGCAAAGCACGTATTAAATATGAT-3′ (SEQ ID NO: 1133)5′-AGCAAAGCACGUAUUAAAUAUGAtc-3′ (SEQ ID NO: 366)3′-GUUCGUUUCGUGCAUAAUUUAUACUAG-5′ (SEQ ID NO: 750) TTR-899 Target:5′-CAAGCAAAGCACGTATTAAATATGATC-3′ (SEQ ID NO: 1134)5′-GCAAAGCACGUAUUAAAUAUGAUct-3′ (SEQ ID NO: 367)3′-UUCGUUUCGUGCAUAAUUUAUACUAGA-5′ (SEQ ID NO: 751) TTR-900 Target:5′-AAGCAAAGCACGTATTAAATATGATCT-3′ (SEQ ID NO: 1135)5′-CAAAGCACGUAUUAAAUAUGAUCtg-3′ (SEQ ID NO: 368)3′-UCGUUUCGUGCAUAAUUUAUACUAGAC-5′ (SEQ ID NO: 752) TTR-901 Target:5′-AGCAAAGCACGTATTAAATATGATCTG-3′ (SEQ ID NO: 1136)5′-AAAGCACGUAUUAAAUAUGAUCUgc-3′ (SEQ ID NO: 369)3′-CGUUUCGUGCAUAAUUUAUACUAGACG-5′ (SEQ ID NO: 753) TTR-902 Target:5′-GCAAAGCACGTATTAAATATGATCTGC-3′ (SEQ ID NO: 1137)5′-AAGCACGUAUUAAAUAUGAUCUGca-3′ (SEQ ID NO: 370)3′-GUUUCGUGCAUAAUUUAUACUAGACGU-5′ (SEQ ID NO: 754) TTR-903 Target:5′-CAAAGCACGTATTAAATATGATCTGCA-3′ (SEQ ID NO: 1138)5′-AGCACGUAUUAAAUAUGAUCUGCag-3′ (SEQ ID NO: 371)3′-UUUCGUGCAUAAUUUAUACUAGACGUC-5′ (SEQ ID NO: 755) TTR-904 Target:5′-AAAGCACGTATTAAATATGATCTGCAG-3′ (SEQ ID NO: 1139)5′-GCACGUAUUAAAUAUGAUCUGCAgc-3′ (SEQ ID NO: 372)3′-UUCGUGCAUAAUUUAUACUAGACGUCG-5′ (SEQ ID NO: 756) TTR-905 Target:5′-AAGCACGTATTAAATATGATCTGCAGC-3′ (SEQ ID NO: 1140)5′-CACGUAUUAAAUAUGAUCUGCAGcc-3′ (SEQ ID NO: 373)3′-UCGUGCAUAAUUUAUACUAGACGUCGG-5′ (SEQ ID NO: 757) TTR-906 Target:5′-AGCACGTATTAAATATGATCTGCAGCC-3′ (SEQ ID NO: 1141)5′-CGUAUUAAAUAUGAUCUGCAGCCat-3′ (SEQ ID NO: 374)3′-GUGCAUAAUUUAUACUAGACGUCGGUA-5′ (SEQ ID NO: 758) TTR-908 Target:5′-CACGTATTAAATATGATCTGCAGCCAT-3′ (SEQ ID NO: 1142)5′-GUAUUAAAUAUGAUCUGCAGCCAtt-3′ (SEQ ID NO: 375)3′-UGCAUAAUUUAUACUAGACGUCGGUAA-5′ (SEQ ID NO: 759) TTR-909 Target:5′-ACGTATTAAATATGATCTGCAGCCATT-3′ (SEQ ID NO: 1143)5′-AUUAAAUAUGAUCUGCAGCCAUUaa-3′ (SEQ ID NO: 376)3′-CAUAAUUUAUACUAGACGUCGGUAAUU-5′ (SEQ ID NO: 760) TTR-911 Target:5′-GTATTAAATATGATCTGCAGCCATTAA-3′ (SEQ ID NO: 1144)5′-UUAAAUAUGAUCUGCAGCCAUUAaa-3′ (SEQ ID NO: 377)3′-AUAAUUUAUACUAGACGUCGGUAAUUU-5′ (SEQ ID NO: 761) TTR-912 Target:5′-TATTAAATATGATCTGCAGCCATTAAA-3′ (SEQ ID NO: 1145)5′-UAAAUAUGAUCUGCAGCCAUUAAaa-3′ (SEQ ID NO: 378)3′-UAAUUUAUACUAGACGUCGGUAAUUUU-5′ (SEQ ID NO: 762) TTR-913 Target:5′-ATTAAATATGATCTGCAGCCATTAAAA-3′ (SEQ ID NO: 1146)5′-AAAUAUGAUCUGCAGCCAUUAAAaa-3′ (SEQ ID NO: 379)3′-AAUUUAUACUAGACGUCGGUAAUUUUU-5′ (SEQ ID NO: 763) TTR-914 Target:5′-TTAAATATGATCTGCAGCCATTAAAAA-3′ (SEQ ID NO: 1147)5′-AAUAUGAUCUGCAGCCAUUAAAAag-3′ (SEQ ID NO: 380)3′-AUUUAUACUAGACGUCGGUAAUUUUUC-5′ (SEQ ID NO: 764) TTR-915 Target:5′-TAAATATGATCTGCAGCCATTAAAAAG-3′ (SEQ ID NO: 1148)5′-AUAUGAUCUGCAGCCAUUAAAAAga-3′ (SEQ ID NO: 381)3′-UUUAUACUAGACGUCGGUAAUUUUUCU-5′ (SEQ ID NO: 765) TTR-916 Target:5′-AAATATGATCTGCAGCCATTAAAAAGA-3′ (SEQ ID NO: 1149)5′-UAUGAUCUGCAGCCAUUAAAAAGac-3′ (SEQ ID NO: 382)3′-UUAUACUAGACGUCGGUAAUUUUUCUG-5′ (SEQ ID NO: 766) TTR-917 Target:5′-AATATGATCTGCAGCCATTAAAAAGAC-3′ (SEQ ID NO: 1150)5′-AUGAUCUGCAGCCAUUAAAAAGAca-3′ (SEQ ID NO: 383)3′-UAUACUAGACGUCGGUAAUUUUUCUGU-5′ (SEQ ID NO: 767) TTR-918 Target:5′-ATATGATCTGCAGCCATTAAAAAGACA-3′ (SEQ ID NO: 1151)5′-UGAUCUGCAGCCAUUAAAAAGACac-3′ (SEQ ID NO: 384)3′-AUACUAGACGUCGGUAAUUUUUCUGUG-5′ (SEQ ID NO: 768) TTR-919 Target:5′-TATGATCTGCAGCCATTAAAAAGACAC-3′ (SEQ ID NO: 1152)

TABLE 3 Selected Human Anti-transthyretin DsiRNAs, Unmodified Duplexes(Asymmetrics) 5′-UGACUAAGUCAAUAAUCAGAAUCAG-3′ (SEQ ID NO: 1153)3′-CAACUGAUUCAGUUAUUAGUCUUAGUC-5′ (SEQ ID NO: 385) TTR-27 Target:5′-GTTGACTAAGTCAATAATCAGAATCAG-3′ (SEQ ID NO: 769)5′-GACUAAGUCAAUAAUCAGAAUCAGC-3′ (SEQ ID NO: 1154)3′-AACUGAUUCAGUUAUUAGUCUUAGUCG-5′ (SEQ ID NO: 386) TTR-28 Target:5′-TTGACTAAGTCAATAATCAGAATCAGC-3′ (SEQ ID NO: 770)5′-ACUAAGUCAAUAAUCAGAAUCAGCA-3′ (SEQ ID NO: 1155)3′-ACUGAUUCAGUUAUUAGUCUUAGUCGU-5′ (SEQ ID NO: 387) TTR-29 Target:5′-TGACTAAGTCAATAATCAGAATCAGCA-3′ (SEQ ID NO: 771)5′-CUAAGUCAAUAAUCAGAAUCAGCAG-3′ (SEQ ID NO: 1156)3′-CUGAUUCAGUUAUUAGUCUUAGUCGUC-5′ (SEQ ID NO: 388) TTR-30 Target:5′-GACTAAGTCAATAATCAGAATCAGCAG-3′ (SEQ ID NO: 772)5′-UAAGUCAAUAAUCAGAAUCAGCAGG-3′ (SEQ ID NO: 1157)3′-UGAUUCAGUUAUUAGUCUUAGUCGUCC-5′ (SEQ ID NO: 389) TTR-31 Target:5′-ACTAAGTCAATAATCAGAATCAGCAGG-3′ (SEQ ID NO: 773)5′-AAGUCAAUAAUCAGAAUCAGCAGGU-3′ (SEQ ID NO: 1158)3′-GAUUCAGUUAUUAGUCUUAGUCGUCCA-5′ (SEQ ID NO: 390) TTR-32 Target:5′-CTAAGTCAATAATCAGAATCAGCAGGT-3′ (SEQ ID NO: 774)5′-AGUCAAUAAUCAGAAUCAGCAGGUU-3′ (SEQ ID NO: 1159)3′-AUUCAGUUAUUAGUCUUAGUCGUCCAA-5′ (SEQ ID NO: 391) TTR-33 Target:5′-TAAGTCAATAATCAGAATCAGCAGGTT-3′ (SEQ ID NO: 775)5′-GUCAAUAAUCAGAAUCAGCAGGUUU-3′ (SEQ ID NO: 1160)3′-UUCAGUUAUUAGUCUUAGUCGUCCAAA-5′ (SEQ ID NO: 392) TTR-34 Target:5′-AAGTCAATAATCAGAATCAGCAGGTTT-3′ (SEQ ID NO: 776)5′-UCAAUAAUCAGAAUCAGCAGGUUUG-3′ (SEQ ID NO: 1161)3′-UCAGUUAUUAGUCUUAGUCGUCCAAAC-5′ (SEQ ID NO: 393) TTR-35 Target:5′-AGTCAATAATCAGAATCAGCAGGTTTG-3′ (SEQ ID NO: 777)5′-CAAUAAUCAGAAUCAGCAGGUUUGC-3′ (SEQ ID NO: 1162)3′-CAGUUAUUAGUCUUAGUCGUCCAAACG-5′ (SEQ ID NO: 394) TTR-36 Target:5′-GTCAATAATCAGAATCAGCAGGTTTGC-3′ (SEQ ID NO: 778)5′-AAUAAUCAGAAUCAGCAGGUUUGCA-3′ (SEQ ID NO: 1163)3′-AGUUAUUAGUCUUAGUCGUCCAAACGU-5′ (SEQ ID NO: 395) TTR-37 Target:5′-TCAATAATCAGAATCAGCAGGTTTGCA-3′ (SEQ ID NO: 779)5′-AUAAUCAGAAUCAGCAGGUUUGCAG-3′ (SEQ ID NO: 1164)3′-GUUAUUAGUCUUAGUCGUCCAAACGUC-5′ (SEQ ID NO: 396) TTR-38 Target:5′-CAATAATCAGAATCAGCAGGTTTGCAG-3′ (SEQ ID NO: 780)5′-UAAUCAGAAUCAGCAGGUUUGCAGU-3′ (SEQ ID NO: 1165)3′-UUAUUAGUCUUAGUCGUCCAAACGUCA-5′ (SEQ ID NO: 397) TTR-39 Target:5′-AATAATCAGAATCAGCAGGTTTGCAGT-3′ (SEQ ID NO: 781)5′-AAUCAGAAUCAGCAGGUUUGCAGUC-3′ (SEQ ID NO: 1166)3′-UAUUAGUCUUAGUCGUCCAAACGUCAG-5′ (SEQ ID NO: 398) TTR-40 Target:5′-ATAATCAGAATCAGCAGGTTTGCAGTC-3′ (SEQ ID NO: 782)5′-AUCAGAAUCAGCAGGUUUGCAGUCA-3′ (SEQ ID NO: 1167)3′-AUUAGUCUUAGUCGUCCAAACGUCAGU-5′ (SEQ ID NO: 399) TTR-41 Target:5′-TAATCAGAATCAGCAGGTTTGCAGTCA-3′ (SEQ ID NO: 783)5′-CAGAAUCAGCAGGUUUGCAGUCAGA-3′ (SEQ ID NO: 1168)3′-UAGUCUUAGUCGUCCAAACGUCAGUCU-5′ (SEQ ID NO: 400) TTR-43 Target:5′-ATCAGAATCAGCAGGTTTGCAGTCAGA-3′ (SEQ ID NO: 784)5′-AGAAUCAGCAGGUUUGCAGUCAGAU-3′ (SEQ ID NO: 1169)3′-AGUCUUAGUCGUCCAAACGUCAGUCUA-5′ (SEQ ID NO: 401) TTR-44 Target:5′-TCAGAATCAGCAGGTTTGCAGTCAGAT-3′ (SEQ ID NO: 785)5′-AAUCAGCAGGUUUGCAGUCAGAUUG-3′ (SEQ ID NO: 1170)3′-UCUUAGUCGUCCAAACGUCAGUCUAAC-5′ (SEQ ID NO: 402) TTR-46 Target:5′-AGAATCAGCAGGTTTGCAGTCAGATTG-3′ (SEQ ID NO: 786)5′-AUCAGCAGGUUUGCAGUCAGAUUGG-3′ (SEQ ID NO: 1171)3′-CUUAGUCGUCCAAACGUCAGUCUAACC-5′ (SEQ ID NO: 403) TTR-47 Target:5′-GAATCAGCAGGTTTGCAGTCAGATTGG-3′ (SEQ ID NO: 787)5′-GCAGUCAGAUUGGCAGGGAUAAGCA-3′ (SEQ ID NO: 1172)3′-AACGUCAGUCUAACCGUCCCUAUUCGU-5′ (SEQ ID NO: 404) TTR-59 Target:5′-TTGCAGTCAGATTGGCAGGGATAAGCA-3′ (SEQ ID NO: 788)5′-GCCUAGCUCAGGAGAAGUGAGUAUA-3′ (SEQ ID NO: 1173)3′-GUCGGAUCGAGUCCUCUUCACUCAUAU-5′ (SEQ ID NO: 405) TTR-84 Target:5′-CAGCCTAGCTCAGGAGAAGTGAGTATA-3′ (SEQ ID NO: 789)5′-UAGCUCAGGAGAAGUGAGUAUAAAA-3′ (SEQ ID NO: 1174)3′-GGAUCGAGUCCUCUUCACUCAUAUUUU-5′ (SEQ ID NO: 406) TTR-87 Target:5′-CCTAGCTCAGGAGAAGTGAGTATAAAA-3′ (SEQ ID NO: 790)5′-AGCUCAGGAGAAGUGAGUAUAAAAG-3′ (SEQ ID NO: 1175)3′-GAUCGAGUCCUCUUCACUCAUAUUUUC-5′ (SEQ ID NO: 407) TTR-88 Target:5′-CTAGCTCAGGAGAAGTGAGTATAAAAG-3′ (SEQ ID NO: 791)5′-GCUCAGGAGAAGUGAGUAUAAAAGC-3′ (SEQ ID NO: 1176)3′-AUCGAGUCCUCUUCACUCAUAUUUUCG-5′ (SEQ ID NO: 408) TTR-89 Target:5′-TAGCTCAGGAGAAGTGAGTATAAAAGC-3′ (SEQ ID NO: 792)5′-CUCAGGAGAAGUGAGUAUAAAAGCC-3′ (SEQ ID NO: 1177)3′-UCGAGUCCUCUUCACUCAUAUUUUCGG-5′ (SEQ ID NO: 409) TTR-90 Target:5′-AGCTCAGGAGAAGTGAGTATAAAAGCC-3′ (SEQ ID NO: 793)5′-CAGGAGAAGUGAGUAUAAAAGCCCC-3′ (SEQ ID NO: 1178)3′-GAGUCCUCUUCACUCAUAUUUUCGGGG-5′ (SEQ ID NO: 410) TTR-92 Target:5′-CTCAGGAGAAGTGAGTATAAAAGCCCC-3′ (SEQ ID NO: 794)5′-GCAGCCAUCACAGAAGUCCACUCAU-3′ (SEQ ID NO: 1179)3′-CUCGUCGGUAGUGUCUUCAGGUGAGUA-5′ (SEQ ID NO: 411) TTR-126 Target:5′-GAGCAGCCATCACAGAAGTCCACTCAT-3′ (SEQ ID NO: 795)5′-CAGCCAUCACAGAAGUCCACUCAUU-3′ (SEQ ID NO: 1180)3′-UCGUCGGUAGUGUCUUCAGGUGAGUAA-5′ (SEQ ID NO: 412) TTR-127 Target:5′-AGCAGCCATCACAGAAGTCCACTCATT-3′ (SEQ ID NO: 796)5′-AGCCAUCACAGAAGUCCACUCAUUC-3′ (SEQ ID NO: 1181)3′-CGUCGGUAGUGUCUUCAGGUGAGUAAG-5′ (SEQ ID NO: 413) TTR-128 Target:5′-GCAGCCATCACAGAAGTCCACTCATTC-3′ (SEQ ID NO: 797)5′-GCCAUCACAGAAGUCCACUCAUUCU-3′ (SEQ ID NO: 1182)3′-GUCGGUAGUGUCUUCAGGUGAGUAAGA-5′ (SEQ ID NO: 414) TTR-129 Target:5′-CAGCCATCACAGAAGTCCACTCATTCT-3′ (SEQ ID NO: 798)5′-CCAUCACAGAAGUCCACUCAUUCUU-3′ (SEQ ID NO: 1183)3′-UCGGUAGUGUCUUCAGGUGAGUAAGAA-5′ (SEQ ID NO: 415) TTR-130 Target:5′-AGCCATCACAGAAGTCCACTCATTCTT-3′ (SEQ ID NO: 799)5′-CAUCACAGAAGUCCACUCAUUCUUG-3′ (SEQ ID NO: 1184)3′-CGGUAGUGUCUUCAGGUGAGUAAGAAC-5′ (SEQ ID NO: 416) TTR-131 Target:5′-GCCATCACAGAAGTCCACTCATTCTTG-3′ (SEQ ID NO: 800)5′-AUCACAGAAGUCCACUCAUUCUUGG-3′ (SEQ ID NO: 1185)3′-GGUAGUGUCUUCAGGUGAGUAAGAACC-5′ (SEQ ID NO: 417) TTR-132 Target:5′-CCATCACAGAAGTCCACTCATTCTTGG-3′ (SEQ ID NO: 801)5′-CACAGAAGUCCACUCAUUCUUGGCA-3′ (SEQ ID NO: 1186)3′-UAGUGUCUUCAGGUGAGUAAGAACCGU-5′ (SEQ ID NO: 418) TTR-134 Target:5′-ATCACAGAAGTCCACTCATTCTTGGCA-3′ (SEQ ID NO: 802)5′-ACAGAAGUCCACUCAUUCUUGGCAG-3′ (SEQ ID NO: 1187)3′-AGUGUCUUCAGGUGAGUAAGAACCGUC-5′ (SEQ ID NO: 419) TTR-135 Target:5′-TCACAGAAGTCCACTCATTCTTGGCAG-3′ (SEQ ID NO: 803)5′-UUCUUGGCAGGAUGGCUUCUCAUCG-3′ (SEQ ID NO: 1188)3′-GUAAGAACCGUCCUACCGAAGAGUAGC-5′ (SEQ ID NO: 420) TTR-150 Target:5′-CATTCTTGGCAGGATGGCTTCTCATCG-3′ (SEQ ID NO: 804)5′-UCUUGGCAGGAUGGCUUCUCAUCGU-3′ (SEQ ID NO: 1189)3′-UAAGAACCGUCCUACCGAAGAGUAGCA-5′ (SEQ ID NO: 421) TTR-151 Target:5′-ATTCTTGGCAGGATGGCTTCTCATCGT-3′ (SEQ ID NO: 805)5′-CUUGGCAGGAUGGCUUCUCAUCGUC-3′ (SEQ ID NO: 1190)3′-AAGAACCGUCCUACCGAAGAGUAGCAG-5′ (SEQ ID NO: 422) TTR-152 Target:5′-TTCTTGGCAGGATGGCTTCTCATCGTC-3′ (SEQ ID NO: 806)5′-UUGGCAGGAUGGCUUCUCAUCGUCU-3′ (SEQ ID NO: 1191)3′-AGAACCGUCCUACCGAAGAGUAGCAGA-5′ (SEQ ID NO: 423) TTR-153 Target:5′-TCTTGGCAGGATGGCTTCTCATCGTCT-3′ (SEQ ID NO: 807)5′-UGGCAGGAUGGCUUCUCAUCGUCUG-3′ (SEQ ID NO: 1192)3′-GAACCGUCCUACCGAAGAGUAGCAGAC-5′ (SEQ ID NO: 424) TTR-154 Target:5′-CTTGGCAGGATGGCTTCTCATCGTCTG-3′ (SEQ ID NO: 808)5′-GGCAGGAUGGCUUCUCAUCGUCUGC-3′ (SEQ ID NO: 1193)3′-AACCGUCCUACCGAAGAGUAGCAGACG-5′ (SEQ ID NO: 425) TTR-155 Target:5′-TTGGCAGGATGGCTTCTCATCGTCTGC-3′ (SEQ ID NO: 809)5′-GCAGGAUGGCUUCUCAUCGUCUGCU-3′ (SEQ ID NO: 1194)3′-ACCGUCCUACCGAAGAGUAGCAGACGA-5′ (SEQ ID NO: 426) TTR-156 Target:5′-TGGCAGGATGGCTTCTCATCGTCTGCT-3′ (SEQ ID NO: 810)5′-CAGGAUGGCUUCUCAUCGUCUGCUC-3′ (SEQ ID NO: 1195)3′-CCGUCCUACCGAAGAGUAGCAGACGAG-5′ (SEQ ID NO: 427) TTR-157 Target:5′-GGCAGGATGGCTTCTCATCGTCTGCTC-3′ (SEQ ID NO: 811)5′-AGGAUGGCUUCUCAUCGUCUGCUCC-3′ (SEQ ID NO: 1196)3′-CGUCCUACCGAAGAGUAGCAGACGAGG-5′ (SEQ ID NO: 428) TTR-158 Target:5′-GCAGGATGGCTTCTCATCGTCTGCTCC-3′ (SEQ ID NO: 812)5′-GGAUGGCUUCUCAUCGUCUGCUCCU-3′ (SEQ ID NO: 1197)3′-GUCCUACCGAAGAGUAGCAGACGAGGA-5′ (SEQ ID NO: 429) TTR-159 Target:5′-CAGGATGGCTTCTCATCGTCTGCTCCT-3′ (SEQ ID NO: 813)5′-GAUGGCUUCUCAUCGUCUGCUCCUC-3′ (SEQ ID NO: 1198)3′-UCCUACCGAAGAGUAGCAGACGAGGAG-5′ (SEQ ID NO: 430) TTR-160 Target:5′-AGGATGGCTTCTCATCGTCTGCTCCTC-3′ (SEQ ID NO: 814)5′-AUGGCUUCUCAUCGUCUGCUCCUCC-3′ (SEQ ID NO: 1199)3′-CCUACCGAAGAGUAGCAGACGAGGAGG-5′ (SEQ ID NO: 431) TTR-161 Target:5′-GGATGGCTTCTCATCGTCTGCTCCTCC-3′ (SEQ ID NO: 815)5′-UGGCUUCUCAUCGUCUGCUCCUCCU-3′ (SEQ ID NO: 1200)3′-CUACCGAAGAGUAGCAGACGAGGAGGA-5′ (SEQ ID NO: 432) TTR-162 Target:5′-GATGGCTTCTCATCGTCTGCTCCTCCT-3′ (SEQ ID NO: 816)5′-GGCUUCUCAUCGUCUGCUCCUCCUC-3′ (SEQ ID NO: 1201)3′-UACCGAAGAGUAGCAGACGAGGAGGAG-5′ (SEQ ID NO: 433) TTR-163 Target:5′-ATGGCTTCTCATCGTCTGCTCCTCCTC-3′ (SEQ ID NO: 817)5′-GCUUCUCAUCGUCUGCUCCUCCUCU-3′ (SEQ ID NO: 1202)3′-ACCGAAGAGUAGCAGACGAGGAGGAGA-5′ (SEQ ID NO: 434) TTR-164 Target:5′-TGGCTTCTCATCGTCTGCTCCTCCTCT-3′ (SEQ ID NO: 818)5′-CUUCUCAUCGUCUGCUCCUCCUCUG-3′ (SEQ ID NO: 1203)3′-CCGAAGAGUAGCAGACGAGGAGGAGAC-5′ (SEQ ID NO: 435) TTR-165 Target:5′-GGCTTCTCATCGTCTGCTCCTCCTCTG-3′ (SEQ ID NO: 819)5′-UCUGCCUUGCUGGACUGGUAUUUGU-3′ (SEQ ID NO: 1204)3′-GGAGACGGAACGACCUGACCAUAAACA-5′ (SEQ ID NO: 436) TTR-186 Target:5′-CCTCTGCCTTGCTGGACTGGTATTTGT-3′ (SEQ ID NO: 820)5′-CUGCCUUGCUGGACUGGUAUUUGUG-3′ (SEQ ID NO: 1205)3′-GAGACGGAACGACCUGACCAUAAACAC-5′ (SEQ ID NO: 437) TTR-187 Target:5′-CTCTGCCTTGCTGGACTGGTATTTGTG-3′ (SEQ ID NO: 821)5′-CCGGUGAAUCCAAGUGUCCUCUGAU-3′ (SEQ ID NO: 1206)3′-GUGGCCACUUAGGUUCACAGGAGACUA-5′ (SEQ ID NO: 438) TTR-234 Target:5′-CACCGGTGAATCCAAGTGTCCTCTGAT-3′ (SEQ ID NO: 822)5′-UGAAUCCAAGUGUCCUCUGAUGGUC-3′ (SEQ ID NO: 1207)3′-CCACUUAGGUUCACAGGAGACUACCAG-5′ (SEQ ID NO: 439) TTR-238 Target:5′-GGTGAATCCAAGTGTCCTCTGATGGTC-3′ (SEQ ID NO: 823)5′-GAAUCCAAGUGUCCUCUGAUGGUCA-3′ (SEQ ID NO: 1208)3′-CACUUAGGUUCACAGGAGACUACCAGU-5′ (SEQ ID NO: 440) TTR-239 Target:5′-GTGAATCCAAGTGTCCTCTGATGGTCA-3′ (SEQ ID NO: 824)5′-AAUCCAAGUGUCCUCUGAUGGUCAA-3′ (SEQ ID NO: 1209)3′-ACUUAGGUUCACAGGAGACUACCAGUU-5′ (SEQ ID NO: 441) TTR-240 Target:5′-TGAATCCAAGTGTCCTCTGATGGTCAA-3′ (SEQ ID NO: 825)5′-AUCCAAGUGUCCUCUGAUGGUCAAA-3′ (SEQ ID NO: 1210)3′-CUUAGGUUCACAGGAGACUACCAGUUU-5′ (SEQ ID NO: 442) TTR-241 Target:5′-GAATCCAAGTGTCCTCTGATGGTCAAA-3′ (SEQ ID NO: 826)5′-UCCAAGUGUCCUCUGAUGGUCAAAG-3′ (SEQ ID NO: 1211)3′-UUAGGUUCACAGGAGACUACCAGUUUC-5′ (SEQ ID NO: 443) TTR-242 Target:5′-AATCCAAGTGTCCTCTGATGGTCAAAG-3′ (SEQ ID NO: 827)5′-CCAAGUGUCCUCUGAUGGUCAAAGU-3′ (SEQ ID NO: 1212)3′-UAGGUUCACAGGAGACUACCAGUUUCA-5′ (SEQ ID NO: 444) TTR-243 Target:5′-ATCCAAGTGTCCTCTGATGGTCAAAGT-3′ (SEQ ID NO: 828)5′-CAAGUGUCCUCUGAUGGUCAAAGUU-3′ (SEQ ID NO: 1213)3′-AGGUUCACAGGAGACUACCAGUUUCAA-5′ (SEQ ID NO: 445) TTR-244 Target:5′-TCCAAGTGTCCTCTGATGGTCAAAGTT-3′ (SEQ ID NO: 829)5′-AAGUGUCCUCUGAUGGUCAAAGUUC-3′ (SEQ ID NO: 1214)3′-GGUUCACAGGAGACUACCAGUUUCAAG-5′ (SEQ ID NO: 446) TTR-245 Target:5′-CCAAGTGTCCTCTGATGGTCAAAGTTC-3′ (SEQ ID NO: 830)5′-AGUGUCCUCUGAUGGUCAAAGUUCU-3′ (SEQ ID NO: 1215)3′-GUUCACAGGAGACUACCAGUUUCAAGA-5′ (SEQ ID NO: 447) TTR-246 Target:5′-CAAGTGTCCTCTGATGGTCAAAGTTCT-3′ (SEQ ID NO: 831)5′-GUGUCCUCUGAUGGUCAAAGUUCUA-3′ (SEQ ID NO: 1216)3′-UUCACAGGAGACUACCAGUUUCAAGAU-5′ (SEQ ID NO: 448) TTR-247 Target:5′-AAGTGTCCTCTGATGGTCAAAGTTCTA-3′ (SEQ ID NO: 832)5′-UGUCCUCUGAUGGUCAAAGUUCUAG-3′ (SEQ ID NO: 1217)3′-UCACAGGAGACUACCAGUUUCAAGAUC-5′ (SEQ ID NO: 449) TTR-248 Target:5′-AGTGTCCTCTGATGGTCAAAGTTCTAG-3′ (SEQ ID NO: 833)5′-GUCCUCUGAUGGUCAAAGUUCUAGA-3′ (SEQ ID NO: 1218)3′-CACAGGAGACUACCAGUUUCAAGAUCU-5′ (SEQ ID NO: 450) TTR-249 Target:5′-GTGTCCTCTGATGGTCAAAGTTCTAGA-3′ (SEQ ID NO: 834)5′-UCCUCUGAUGGUCAAAGUUCUAGAU-3′ (SEQ ID NO: 1219)3′-ACAGGAGACUACCAGUUUCAAGAUCUA-5′ (SEQ ID NO: 451) TTR-250 Target:5′-TGTCCTCTGATGGTCAAAGTTCTAGAT-3′ (SEQ ID NO: 835)5′-CCUCUGAUGGUCAAAGUUCUAGAUG-3′ (SEQ ID NO: 1220)3′-CAGGAGACUACCAGUUUCAAGAUCUAC-5′ (SEQ ID NO: 452) TTR-251 Target:5′-GTCCTCTGATGGTCAAAGTTCTAGATG-3′ (SEQ ID NO: 836)5′-CUCUGAUGGUCAAAGUUCUAGAUGC-3′ (SEQ ID NO: 1221)3′-AGGAGACUACCAGUUUCAAGAUCUACG-5′ (SEQ ID NO: 453) TTR-252 Target:5′-TCCTCTGATGGTCAAAGTTCTAGATGC-3′ (SEQ ID NO: 837)5′-UCUGAUGGUCAAAGUUCUAGAUGCU-3′ (SEQ ID NO: 1222)3′-GGAGACUACCAGUUUCAAGAUCUACGA-5′ (SEQ ID NO: 454) TTR-253 Target:5′-CCTCTGATGGTCAAAGTTCTAGATGCT-3′ (SEQ ID NO: 838)5′-CUGAUGGUCAAAGUUCUAGAUGCUG-3′ (SEQ ID NO: 1223)3′-GAGACUACCAGUUUCAAGAUCUACGAC-5′ (SEQ ID NO: 455) TTR-254 Target:5′-CTCTGATGGTCAAAGTTCTAGATGCTG-3′ (SEQ ID NO: 839)5′-UGAUGGUCAAAGUUCUAGAUGCUGU-3′ (SEQ ID NO: 1224)3′-AGACUACCAGUUUCAAGAUCUACGACA-5′ (SEQ ID NO: 456) TTR-255 Target:5′-TCTGATGGTCAAAGTTCTAGATGCTGT-3′ (SEQ ID NO: 840)5′-GAUGGUCAAAGUUCUAGAUGCUGUC-3′ (SEQ ID NO: 1225)3′-GACUACCAGUUUCAAGAUCUACGACAG-5′ (SEQ ID NO: 457) TTR-256 Target:5′-CTGATGGTCAAAGTTCTAGATGCTGTC-3′ (SEQ ID NO: 841)5′-AUGGUCAAAGUUCUAGAUGCUGUCC-3′ (SEQ ID NO: 1226)3′-ACUACCAGUUUCAAGAUCUACGACAGG-5′ (SEQ ID NO: 458) TTR-257 Target:5′-TGATGGTCAAAGTTCTAGATGCTGTCC-3′ (SEQ ID NO: 842)5′-UGGUCAAAGUUCUAGAUGCUGUCCG-3′ (SEQ ID NO: 1227)3′-CUACCAGUUUCAAGAUCUACGACAGGC-5′ (SEQ ID NO: 459) TTR-258 Target:5′-GATGGTCAAAGTTCTAGATGCTGTCCG-3′ (SEQ ID NO: 843)5′-GCCAUUUGCCUCUGGGAAAACCAGU-3′ (SEQ ID NO: 1228)3′-CUCGGUAAACGGAGACCCUUUUGGUCA-5′ (SEQ ID NO: 460) TTR-346 Target:5′-GAGCCATTTGCCTCTGGGAAAACCAGT-3′ (SEQ ID NO: 844)5′-CCAUUUGCCUCUGGGAAAACCAGUG-3′ (SEQ ID NO: 1229)3′-UCGGUAAACGGAGACCCUUUUGGUCAC-5′ (SEQ ID NO: 461) TTR-347 Target:5′-AGCCATTTGCCTCTGGGAAAACCAGTG-3′ (SEQ ID NO: 845)5′-CAUUUGCCUCUGGGAAAACCAGUGA-3′ (SEQ ID NO: 1230)3′-CGGUAAACGGAGACCCUUUUGGUCACU-5′ (SEQ ID NO: 462) TTR-348 Target:5′-GCCATTTGCCTCTGGGAAAACCAGTGA-3′ (SEQ ID NO: 846)5′-AUUUGCCUCUGGGAAAACCAGUGAG-3′ (SEQ ID NO: 1231)3′-GGUAAACGGAGACCCUUUUGGUCACUC-5′ (SEQ ID NO: 463) TTR-349 Target:5′-CCATTTGCCTCTGGGAAAACCAGTGAG-3′ (SEQ ID NO: 847)5′-UUUGCCUCUGGGAAAACCAGUGAGU-3′ (SEQ ID NO: 1232)3′-GUAAACGGAGACCCUUUUGGUCACUCA-5′ (SEQ ID NO: 464) TTR-350 Target:5′-CATTTGCCTCTGGGAAAACCAGTGAGT-3′ (SEQ ID NO: 848)5′-UUGCCUCUGGGAAAACCAGUGAGUC-3′ (SEQ ID NO: 1233)3′-UAAACGGAGACCCUUUUGGUCACUCAG-5′ (SEQ ID NO: 465) TTR-351 Target:5′-ATTTGCCTCTGGGAAAACCAGTGAGTC-3′ (SEQ ID NO: 849)5′-UGCCUCUGGGAAAACCAGUGAGUCU-3′ (SEQ ID NO: 1234)3′-AAACGGAGACCCUUUUGGUCACUCAGA-5′ (SEQ ID NO: 466) TTR-352 Target:5′-TTTGCCTCTGGGAAAACCAGTGAGTCT-3′ (SEQ ID NO: 850)5′-GCCUCUGGGAAAACCAGUGAGUCUG-3′ (SEQ ID NO: 1235)3′-AACGGAGACCCUUUUGGUCACUCAGAC-5′ (SEQ ID NO: 467) TTR-353 Target:5′-TTGCCTCTGGGAAAACCAGTGAGTCTG-3′ (SEQ ID NO: 851)5′-CCUCUGGGAAAACCAGUGAGUCUGG-3′ (SEQ ID NO: 1236)3′-ACGGAGACCCUUUUGGUCACUCAGACC-5′ (SEQ ID NO: 468) TTR-354 Target:5′-TGCCTCTGGGAAAACCAGTGAGTCTGG-3′ (SEQ ID NO: 852)5′-CUCUGGGAAAACCAGUGAGUCUGGA-3′ (SEQ ID NO: 1237)3′-CGGAGACCCUUUUGGUCACUCAGACCU-5′ (SEQ ID NO: 469) TTR-355 Target:5′-GCCTCTGGGAAAACCAGTGAGTCTGGA-3′ (SEQ ID NO: 853)5′-UCUGGGAAAACCAGUGAGUCUGGAG-3′ (SEQ ID NO: 1238)3′-GGAGACCCUUUUGGUCACUCAGACCUC-5′ (SEQ ID NO: 470) TTR-356 Target:5′-CCTCTGGGAAAACCAGTGAGTCTGGAG-3′ (SEQ ID NO: 854)5′-CUGGGAAAACCAGUGAGUCUGGAGA-3′ (SEQ ID NO: 1239)3′-GAGACCCUUUUGGUCACUCAGACCUCU-5′ (SEQ ID NO: 471) TTR-357 Target:5′-CTCTGGGAAAACCAGTGAGTCTGGAGA-3′ (SEQ ID NO: 855)5′-UGGGAAAACCAGUGAGUCUGGAGAG-3′ (SEQ ID NO: 1240)3′-AGACCCUUUUGGUCACUCAGACCUCUC-5′ (SEQ ID NO: 472) TTR-358 Target:5′-TCTGGGAAAACCAGTGAGTCTGGAGAG-3′ (SEQ ID NO: 856)5′-GGGAAAACCAGUGAGUCUGGAGAGC-3′ (SEQ ID NO: 1241)3′-GACCCUUUUGGUCACUCAGACCUCUCG-5′ (SEQ ID NO: 473) TTR-359 Target:5′-CTGGGAAAACCAGTGAGTCTGGAGAGC-3′ (SEQ ID NO: 857)5′-GGAAAACCAGUGAGUCUGGAGAGCU-3′ (SEQ ID NO: 1242)3′-ACCCUUUUGGUCACUCAGACCUCUCGA-5′ (SEQ ID NO: 474) TTR-360 Target:5′-TGGGAAAACCAGTGAGTCTGGAGAGCT-3′ (SEQ ID NO: 858)5′-GAAAACCAGUGAGUCUGGAGAGCUG-3′ (SEQ ID NO: 1243)3′-CCCUUUUGGUCACUCAGACCUCUCGAC-5′ (SEQ ID NO: 475) TTR-361 Target:5′-GGGAAAACCAGTGAGTCTGGAGAGCTG-3′ (SEQ ID NO: 859)5′-AGCUGCAUGGGCUCACAACUGAGGA-3′ (SEQ ID NO: 1244)3′-UCUCGACGUACCCGAGUGUUGACUCCU-5′ (SEQ ID NO: 476) TTR-381 Target:5′-AGAGCTGCATGGGCTCACAACTGAGGA-3′ (SEQ ID NO: 860)5′-GCUGCAUGGGCUCACAACUGAGGAG-3′ (SEQ ID NO: 1245)3′-CUCGACGUACCCGAGUGUUGACUCCUC-5′ (SEQ ID NO: 477) TTR-382 Target:5′-GAGCTGCATGGGCTCACAACTGAGGAG-3′ (SEQ ID NO: 861)5′-CUGCAUGGGCUCACAACUGAGGAGG-3′ (SEQ ID NO: 1246)3′-UCGACGUACCCGAGUGUUGACUCCUCC-5′ (SEQ ID NO: 478) TTR-383 Target:5′-AGCTGCATGGGCTCACAACTGAGGAGG-3′ (SEQ ID NO: 862)5′-UGCAUGGGCUCACAACUGAGGAGGA-3′ (SEQ ID NO: 1247)3′-CGACGUACCCGAGUGUUGACUCCUCCU-5′ (SEQ ID NO: 479) TTR-384 Target:5′-GCTGCATGGGCTCACAACTGAGGAGGA-3′ (SEQ ID NO: 863)5′-GCAUGGGCUCACAACUGAGGAGGAA-3′ (SEQ ID NO: 1248)3′-GACGUACCCGAGUGUUGACUCCUCCUU-5′ (SEQ ID NO: 480) TTR-385 Target:5′-CTGCATGGGCTCACAACTGAGGAGGAA-3′ (SEQ ID NO: 864)5′-CAUGGGCUCACAACUGAGGAGGAAU-3′ (SEQ ID NO: 1249)3′-ACGUACCCGAGUGUUGACUCCUCCUUA-5′ (SEQ ID NO: 481) TTR-386 Target:5′-TGCATGGGCTCACAACTGAGGAGGAAT-3′ (SEQ ID NO: 865)5′-AUGGGCUCACAACUGAGGAGGAAUU-3′ (SEQ ID NO: 1250)3′-CGUACCCGAGUGUUGACUCCUCCUUAA-5′ (SEQ ID NO: 482) TTR-387 Target:5′-GCATGGGCTCACAACTGAGGAGGAATT-3′ (SEQ ID NO: 866)5′-UGGGCUCACAACUGAGGAGGAAUUU-3′ (SEQ ID NO: 1251)3′-GUACCCGAGUGUUGACUCCUCCUUAAA-5′ (SEQ ID NO: 483) TTR-388 Target:5′-CATGGGCTCACAACTGAGGAGGAATTT-3′ (SEQ ID NO: 867)5′-GGGCUCACAACUGAGGAGGAAUUUG-3′ (SEQ ID NO: 1252)3′-UACCCGAGUGUUGACUCCUCCUUAAAC-5′ (SEQ ID NO: 484) TTR-389 Target:5′-ATGGGCTCACAACTGAGGAGGAATTTG-3′ (SEQ ID NO: 868)5′-GGCUCACAACUGAGGAGGAAUUUGU-3′ (SEQ ID NO: 1253)3′-ACCCGAGUGUUGACUCCUCCUUAAACA-5′ (SEQ ID NO: 485) TTR-390 Target:5′-TGGGCTCACAACTGAGGAGGAATTTGT-3′ (SEQ ID NO: 869)5′-GCUCACAACUGAGGAGGAAUUUGUA-3′ (SEQ ID NO: 1254)3′-CCCGAGUGUUGACUCCUCCUUAAACAU-5′ (SEQ ID NO: 486) TTR-391 Target:5′-GGGCTCACAACTGAGGAGGAATTTGTA-3′ (SEQ ID NO: 870)5′-CUCACAACUGAGGAGGAAUUUGUAG-3′ (SEQ ID NO: 1255)3′-CCGAGUGUUGACUCCUCCUUAAACAUC-5′ (SEQ ID NO: 487) TTR-392 Target:5′-GGCTCACAACTGAGGAGGAATTTGTAG-3′ (SEQ ID NO: 871)5′-UCACAACUGAGGAGGAAUUUGUAGA-3′ (SEQ ID NO: 1256)3′-CGAGUGUUGACUCCUCCUUAAACAUCU-5′ (SEQ ID NO: 488) TTR-393 Target:5′-GCTCACAACTGAGGAGGAATTTGTAGA-3′ (SEQ ID NO: 872)5′-CACAACUGAGGAGGAAUUUGUAGAA-3′ (SEQ ID NO: 1257)3′-GAGUGUUGACUCCUCCUUAAACAUCUU-5′ (SEQ ID NO: 489) TTR-394 Target:5′-CTCACAACTGAGGAGGAATTTGTAGAA-3′ (SEQ ID NO: 873)5′-ACAACUGAGGAGGAAUUUGUAGAAG-3′ (SEQ ID NO: 1258)3′-AGUGUUGACUCCUCCUUAAACAUCUUC-5′ (SEQ ID NO: 490) TTR-395 Target:5′-TCACAACTGAGGAGGAATTTGTAGAAG-3′ (SEQ ID NO: 874)5′-CAACUGAGGAGGAAUUUGUAGAAGG-3′ (SEQ ID NO: 1259)3′-GUGUUGACUCCUCCUUAAACAUCUUCC-5′ (SEQ ID NO: 491) TTR-396 Target:5′-CACAACTGAGGAGGAATTTGTAGAAGG-3′ (SEQ ID NO: 875)5′-ACUGAGGAGGAAUUUGUAGAAGGGA-3′ (SEQ ID NO: 1260)3′-GUUGACUCCUCCUUAAACAUCUUCCCU-5′ (SEQ ID NO: 492) TTR-398 Target:5′-CAACTGAGGAGGAATTTGTAGAAGGGA-3′ (SEQ ID NO: 876)5′-CUGAGGAGGAAUUUGUAGAAGGGAU-3′ (SEQ ID NO: 1261)3′-UUGACUCCUCCUUAAACAUCUUCCCUA-5′ (SEQ ID NO: 493) TTR-399 Target:5′-AACTGAGGAGGAATTTGTAGAAGGGAT-3′ (SEQ ID NO: 877)5′-UGAGGAGGAAUUUGUAGAAGGGAUA-3′ (SEQ ID NO: 1262)3′-UGACUCCUCCUUAAACAUCUUCCCUAU-5′ (SEQ ID NO: 494) TTR-400 Target:5′-ACTGAGGAGGAATTTGTAGAAGGGATA-3′ (SEQ ID NO: 878)5′-GAGGAGGAAUUUGUAGAAGGGAUAU-3′ (SEQ ID NO: 1263)3′-GACUCCUCCUUAAACAUCUUCCCUAUA-5′ (SEQ ID NO: 495) TTR-401 Target:5′-CTGAGGAGGAATTTGTAGAAGGGATAT-3′ (SEQ ID NO: 879)5′-AGGAGGAAUUUGUAGAAGGGAUAUA-3′ (SEQ ID NO: 1264)3′-ACUCCUCCUUAAACAUCUUCCCUAUAU-5′ (SEQ ID NO: 496) TTR-402 Target:5′-TGAGGAGGAATTTGTAGAAGGGATATA-3′ (SEQ ID NO: 880)5′-GGAGGAAUUUGUAGAAGGGAUAUAC-3′ (SEQ ID NO: 1265)3′-CUCCUCCUUAAACAUCUUCCCUAUAUG-5′ (SEQ ID NO: 497) TTR-403 Target:5′-GAGGAGGAATTTGTAGAAGGGATATAC-3′ (SEQ ID NO: 881)5′-GAGGAAUUUGUAGAAGGGAUAUACA-3′ (SEQ ID NO: 1266)3′-UCCUCCUUAAACAUCUUCCCUAUAUGU-5′ (SEQ ID NO: 498) TTR-404 Target:5′-AGGAGGAATTTGTAGAAGGGATATACA-3′ (SEQ ID NO: 882)5′-AGGAAUUUGUAGAAGGGAUAUACAA-3′ (SEQ ID NO: 1267)3′-CCUCCUUAAACAUCUUCCCUAUAUGUU-5′ (SEQ ID NO: 499) TTR-405 Target:5′-GGAGGAATTTGTAGAAGGGATATACAA-3′ (SEQ ID NO: 883)5′-GGAAUUUGUAGAAGGGAUAUACAAA-3′ (SEQ ID NO: 1268)3′-CUCCUUAAACAUCUUCCCUAUAUGUUU-5′ (SEQ ID NO: 500) TTR-406 Target:5′-GAGGAATTTGTAGAAGGGATATACAAA-3′ (SEQ ID NO: 884)5′-GAAUUUGUAGAAGGGAUAUACAAAG-3′ (SEQ ID NO: 1269)3′-UCCUUAAACAUCUUCCCUAUAUGUUUC-5′ (SEQ ID NO: 501) TTR-407 Target:5′-AGGAATTTGTAGAAGGGATATACAAAG-3′ (SEQ ID NO: 885)5′-AAUUUGUAGAAGGGAUAUACAAAGU-3′ (SEQ ID NO: 1270)3′-CCUUAAACAUCUUCCCUAUAUGUUUCA-5′ (SEQ ID NO: 502) TTR-408 Target:5′-GGAATTTGTAGAAGGGATATACAAAGT-3′ (SEQ ID NO: 886)5′-AUUUGUAGAAGGGAUAUACAAAGUG-3′ (SEQ ID NO: 1271)3′-CUUAAACAUCUUCCCUAUAUGUUUCAC-5′ (SEQ ID NO: 503) TTR-409 Target:5′-GAATTTGTAGAAGGGATATACAAAGTG-3′ (SEQ ID NO: 887)5′-UUUGUAGAAGGGAUAUACAAAGUGG-3′ (SEQ ID NO: 1272)3′-UUAAACAUCUUCCCUAUAUGUUUCACC-5′ (SEQ ID NO: 504) TTR-410 Target:5′-AATTTGTAGAAGGGATATACAAAGTGG-3′ (SEQ ID NO: 888)5′-UUGUAGAAGGGAUAUACAAAGUGGA-3′ (SEQ ID NO: 1273)3′-UAAACAUCUUCCCUAUAUGUUUCACCU-5′ (SEQ ID NO: 505) TTR-411 Target:5′-ATTTGTAGAAGGGATATACAAAGTGGA-3′ (SEQ ID NO: 889)5′-UGUAGAAGGGAUAUACAAAGUGGAA-3′ (SEQ ID NO: 1274)3′-AAACAUCUUCCCUAUAUGUUUCACCUU-5′ (SEQ ID NO: 506) TTR-412 Target:5′-TTTGTAGAAGGGATATACAAAGTGGAA-3′ (SEQ ID NO: 890)5′-GUAGAAGGGAUAUACAAAGUGGAAA-3′ (SEQ ID NO: 1275)3′-AACAUCUUCCCUAUAUGUUUCACCUUU-5′ (SEQ ID NO: 507) TTR-413 Target:5′-TTGTAGAAGGGATATACAAAGTGGAAA-3′ (SEQ ID NO: 891)5′-UAGAAGGGAUAUACAAAGUGGAAAU-3′ (SEQ ID NO: 1276)3′-ACAUCUUCCCUAUAUGUUUCACCUUUA-5′ (SEQ ID NO: 508) TTR-414 Target:5′-TGTAGAAGGGATATACAAAGTGGAAAT-3′ (SEQ ID NO: 892)5′-AGAAGGGAUAUACAAAGUGGAAAUA-3′ (SEQ ID NO: 1277)3′-CAUCUUCCCUAUAUGUUUCACCUUUAU-5′ (SEQ ID NO: 509) TTR-415 Target:5′-GTAGAAGGGATATACAAAGTGGAAATA-3′ (SEQ ID NO: 893)5′-GAAGGGAUAUACAAAGUGGAAAUAG-3′ (SEQ ID NO: 1278)3′-AUCUUCCCUAUAUGUUUCACCUUUAUC-5′ (SEQ ID NO: 510) TTR-416 Target:5′-TAGAAGGGATATACAAAGTGGAAATAG-3′ (SEQ ID NO: 894)5′-AAGGGAUAUACAAAGUGGAAAUAGA-3′ (SEQ ID NO: 1279)3′-UCUUCCCUAUAUGUUUCACCUUUAUCU-5′ (SEQ ID NO: 511) TTR-417 Target:5′-AGAAGGGATATACAAAGTGGAAATAGA-3′ (SEQ ID NO: 895)5′-AGGGAUAUACAAAGUGGAAAUAGAC-3′ (SEQ ID NO: 1280)3′-CUUCCCUAUAUGUUUCACCUUUAUCUG-5′ (SEQ ID NO: 512) TTR-418 Target:5′-GAAGGGATATACAAAGTGGAAATAGAC-3′ (SEQ ID NO: 896)5′-GGGAUAUACAAAGUGGAAAUAGACA-3′ (SEQ ID NO: 1281)3′-UUCCCUAUAUGUUUCACCUUUAUCUGU-5′ (SEQ ID NO: 513) TTR-419 Target:5′-AAGGGATATACAAAGTGGAAATAGACA-3′ (SEQ ID NO: 897)5′-GGAUAUACAAAGUGGAAAUAGACAC-3′ (SEQ ID NO: 1282)3′-UCCCUAUAUGUUUCACCUUUAUCUGUG-5′ (SEQ ID NO: 514) TTR-420 Target:5′-AGGGATATACAAAGTGGAAATAGACAC-3′ (SEQ ID NO: 898)5′-GAUAUACAAAGUGGAAAUAGACACC-3′ (SEQ ID NO: 1283)3′-CCCUAUAUGUUUCACCUUUAUCUGUGG-5′ (SEQ ID NO: 515) TTR-421 Target:5′-GGGATATACAAAGTGGAAATAGACACC-3′ (SEQ ID NO: 899)5′-AUAUACAAAGUGGAAAUAGACACCA-3′ (SEQ ID NO: 1284)3′-CCUAUAUGUUUCACCUUUAUCUGUGGU-5′ (SEQ ID NO: 516) TTR-422 Target:5′-GGATATACAAAGTGGAAATAGACACCA-3′ (SEQ ID NO: 900)5′-UAUACAAAGUGGAAAUAGACACCAA-3′ (SEQ ID NO: 1285)3′-CUAUAUGUUUCACCUUUAUCUGUGGUU-5′ (SEQ ID NO: 517) TTR-423 Target:5′-GATATACAAAGTGGAAATAGACACCAA-3′ (SEQ ID NO: 901)5′-AUACAAAGUGGAAAUAGACACCAAA-3′ (SEQ ID NO: 1286)3′-UAUAUGUUUCACCUUUAUCUGUGGUUU-5′ (SEQ ID NO: 518) TTR-424 Target:5′-ATATACAAAGTGGAAATAGACACCAAA-3′ (SEQ ID NO: 902)5′-UACAAAGUGGAAAUAGACACCAAAU-3′ (SEQ ID NO: 1287)3′-AUAUGUUUCACCUUUAUCUGUGGUUUA-5′ (SEQ ID NO: 519) TTR-425 Target:5′-TATACAAAGTGGAAATAGACACCAAAT-3′ (SEQ ID NO: 903)5′-ACAAAGUGGAAAUAGACACCAAAUC-3′ (SEQ ID NO: 1288)3′-UAUGUUUCACCUUUAUCUGUGGUUUAG-5′ (SEQ ID NO: 520) TTR-426 Target:5′-ATACAAAGTGGAAATAGACACCAAATC-3′ (SEQ ID NO: 904)5′-CAAAGUGGAAAUAGACACCAAAUCU-3′ (SEQ ID NO: 1289)3′-AUGUUUCACCUUUAUCUGUGGUUUAGA-5′ (SEQ ID NO: 521) TTR-427 Target:5′-TACAAAGTGGAAATAGACACCAAATCT-3′ (SEQ ID NO: 905)5′-AAAGUGGAAAUAGACACCAAAUCUU-3′ (SEQ ID NO: 1290)3′-UGUUUCACCUUUAUCUGUGGUUUAGAA-5′ (SEQ ID NO: 522) TTR-428 Target:5′-ACAAAGTGGAAATAGACACCAAATCTT-3′ (SEQ ID NO: 906)5′-AAGUGGAAAUAGACACCAAAUCUUA-3′ (SEQ ID NO: 1291)3′-GUUUCACCUUUAUCUGUGGUUUAGAAU-5′ (SEQ ID NO: 523) TTR-429 Target:5′-CAAAGTGGAAATAGACACCAAATCTTA-3′ (SEQ ID NO: 907)5′-AGUGGAAAUAGACACCAAAUCUUAC-3′ (SEQ ID NO: 1292)3′-UUUCACCUUUAUCUGUGGUUUAGAAUG-5′ (SEQ ID NO: 524) TTR-430 Target:5′-AAAGTGGAAATAGACACCAAATCTTAC-3′ (SEQ ID NO: 908)5′-GUGGAAAUAGACACCAAAUCUUACU-3′ (SEQ ID NO: 1293)3′-UUCACCUUUAUCUGUGGUUUAGAAUGA-5′ (SEQ ID NO: 525) TTR-431 Target:5′-AAGTGGAAATAGACACCAAATCTTACT-3′ (SEQ ID NO: 909)5′-UGGAAAUAGACACCAAAUCUUACUG-3′ (SEQ ID NO: 1294)3′-UCACCUUUAUCUGUGGUUUAGAAUGAC-5′ (SEQ ID NO: 526) TTR-432 Target:5′-AGTGGAAATAGACACCAAATCTTACTG-3′ (SEQ ID NO: 910)5′-GGAAAUAGACACCAAAUCUUACUGG-3′ (SEQ ID NO: 1295)3′-CACCUUUAUCUGUGGUUUAGAAUGACC-5′ (SEQ ID NO: 527) TTR-433 Target:5′-GTGGAAATAGACACCAAATCTTACTGG-3′ (SEQ ID NO: 911)5′-GAAAUAGACACCAAAUCUUACUGGA-3′ (SEQ ID NO: 1296)3′-ACCUUUAUCUGUGGUUUAGAAUGACCU-5′ (SEQ ID NO: 528) TTR-434 Target:5′-TGGAAATAGACACCAAATCTTACTGGA-3′ (SEQ ID NO: 912)5′-AAAUAGACACCAAAUCUUACUGGAA-3′ (SEQ ID NO: 1297)3′-CCUUUAUCUGUGGUUUAGAAUGACCUU-5′ (SEQ ID NO: 529) TTR-435 Target:5′-GGAAATAGACACCAAATCTTACTGGAA-3′ (SEQ ID NO: 913)5′-AAUAGACACCAAAUCUUACUGGAAG-3′ (SEQ ID NO: 1298)3′-CUUUAUCUGUGGUUUAGAAUGACCUUC-5′ (SEQ ID NO: 530) TTR-436 Target:5′-GAAATAGACACCAAATCTTACTGGAAG-3′ (SEQ ID NO: 914)5′-AUAGACACCAAAUCUUACUGGAAGG-3′ (SEQ ID NO: 1299)3′-UUUAUCUGUGGUUUAGAAUGACCUUCC-5′ (SEQ ID NO: 531) TTR-437 Target:5′-AAATAGACACCAAATCTTACTGGAAGG-3′ (SEQ ID NO: 915)5′-AGACACCAAAUCUUACUGGAAGGCA-3′ (SEQ ID NO: 1300)3′-UAUCUGUGGUUUAGAAUGACCUUCCGU-5′ (SEQ ID NO: 532) TTR-439 Target:5′-ATAGACACCAAATCTTACTGGAAGGCA-3′ (SEQ ID NO: 916)5′-GACACCAAAUCUUACUGGAAGGCAC-3′ (SEQ ID NO: 1301)3′-AUCUGUGGUUUAGAAUGACCUUCCGUG-5′ (SEQ ID NO: 533) TTR-440 Target:5′-TAGACACCAAATCTTACTGGAAGGCAC-3′ (SEQ ID NO: 917)5′-CACUUGGCAUCUCCCCAUUCCAUGA-3′ (SEQ ID NO: 1302)3′-CCGUGAACCGUAGAGGGGUAAGGUACU-5′ (SEQ ID NO: 534) TTR-462 Target:5′-GGCACTTGGCATCTCCCCATTCCATGA-3′ (SEQ ID NO: 918)5′-ACUUGGCAUCUCCCCAUUCCAUGAG-3′ (SEQ ID NO: 1303)3′-CGUGAACCGUAGAGGGGUAAGGUACUC-5′ (SEQ ID NO: 535) TTR-463 Target:5′-GCACTTGGCATCTCCCCATTCCATGAG-3′ (SEQ ID NO: 919)5′-CUUGGCAUCUCCCCAUUCCAUGAGC-3′ (SEQ ID NO: 1304)3′-GUGAACCGUAGAGGGGUAAGGUACUCG-5′ (SEQ ID NO: 536) TTR-464 Target:5′-CACTTGGCATCTCCCCATTCCATGAGC-3′ (SEQ ID NO: 920)5′-UUGGCAUCUCCCCAUUCCAUGAGCA-3′ (SEQ ID NO: 1305)3′-UGAACCGUAGAGGGGUAAGGUACUCGU-5′ (SEQ ID NO: 537) TTR-465 Target:5′-ACTTGGCATCTCCCCATTCCATGAGCA-3′ (SEQ ID NO: 921)5′-UGGCAUCUCCCCAUUCCAUGAGCAU-3′ (SEQ ID NO: 1306)3′-GAACCGUAGAGGGGUAAGGUACUCGUA-5′ (SEQ ID NO: 538) TTR-466 Target:5′-CTTGGCATCTCCCCATTCCATGAGCAT-3′ (SEQ ID NO: 922)5′-GGCAUCUCCCCAUUCCAUGAGCAUG-3′ (SEQ ID NO: 1307)3′-AACCGUAGAGGGGUAAGGUACUCGUAC-5′ (SEQ ID NO: 539) TTR-467 Target:5′-TTGGCATCTCCCCATTCCATGAGCATG-3′ (SEQ ID NO: 923)5′-GCAUCUCCCCAUUCCAUGAGCAUGC-3′ (SEQ ID NO: 1308)3′-ACCGUAGAGGGGUAAGGUACUCGUACG-5′ (SEQ ID NO: 540) TTR-468 Target:5′-TGGCATCTCCCCATTCCATGAGCATGC-3′ (SEQ ID NO: 924)5′-CAUCUCCCCAUUCCAUGAGCAUGCA-3′ (SEQ ID NO: 1309)3′-CCGUAGAGGGGUAAGGUACUCGUACGU-5′ (SEQ ID NO: 541) TTR-469 Target:5′-GGCATCTCCCCATTCCATGAGCATGCA-3′ (SEQ ID NO: 925)5′-AUCUCCCCAUUCCAUGAGCAUGCAG-3′ (SEQ ID NO: 1310)3′-CGUAGAGGGGUAAGGUACUCGUACGUC-5′ (SEQ ID NO: 542) TTR-470 Target:5′-GCATCTCCCCATTCCATGAGCATGCAG-3′ (SEQ ID NO: 926)5′-UCUCCCCAUUCCAUGAGCAUGCAGA-3′ (SEQ ID NO: 1311)3′-GUAGAGGGGUAAGGUACUCGUACGUCU-5′ (SEQ ID NO: 543) TTR-471 Target:5′-CATCTCCCCATTCCATGAGCATGCAGA-3′ (SEQ ID NO: 927)5′-CUCCCCAUUCCAUGAGCAUGCAGAG-3′ (SEQ ID NO: 1312)3′-UAGAGGGGUAAGGUACUCGUACGUCUC-5′ (SEQ ID NO: 544) TTR-472 Target:5′-ATCTCCCCATTCCATGAGCATGCAGAG-3′ (SEQ ID NO: 928)5′-UCCCCAUUCCAUGAGCAUGCAGAGG-3′ (SEQ ID NO: 1313)3′-AGAGGGGUAAGGUACUCGUACGUCUCC-5′ (SEQ ID NO: 545) TTR-473 Target:5′-TCTCCCCATTCCATGAGCATGCAGAGG-3′ (SEQ ID NO: 929)5′-CCCCAUUCCAUGAGCAUGCAGAGGU-3′ (SEQ ID NO: 1314)3′-GAGGGGUAAGGUACUCGUACGUCUCCA-5′ (SEQ ID NO: 546) TTR-474 Target:5′-CTCCCCATTCCATGAGCATGCAGAGGT-3′ (SEQ ID NO: 930)5′-CAUGAGCAUGCAGAGGUGGUAUUCA-3′ (SEQ ID NO: 1315)3′-AGGUACUCGUACGUCUCCACCAUAAGU-5′ (SEQ ID NO: 547) TTR-482 Target:5′-TCCATGAGCATGCAGAGGTGGTATTCA-3′ (SEQ ID NO: 931)5′-AUGAGCAUGCAGAGGUGGUAUUCAC-3′ (SEQ ID NO: 1316)3′-GGUACUCGUACGUCUCCACCAUAAGUG-5′ (SEQ ID NO: 548) TTR-483 Target:5′-CCATGAGCATGCAGAGGTGGTATTCAC-3′ (SEQ ID NO: 932)5′-UGAGCAUGCAGAGGUGGUAUUCACA-3′ (SEQ ID NO: 1317)3′-GUACUCGUACGUCUCCACCAUAAGUGU-5′ (SEQ ID NO: 549) TTR-484 Target:5′-CATGAGCATGCAGAGGTGGTATTCACA-3′ (SEQ ID NO: 933)5′-GAGCAUGCAGAGGUGGUAUUCACAG-3′ (SEQ ID NO: 1318)3′-UACUCGUACGUCUCCACCAUAAGUGUC-5′ (SEQ ID NO: 550) TTR-485 Target:5′-ATGAGCATGCAGAGGTGGTATTCACAG-3′ (SEQ ID NO: 934)5′-AUGCAGAGGUGGUAUUCACAGCCAA-3′ (SEQ ID NO: 1319)3′-CGUACGUCUCCACCAUAAGUGUCGGUU-5′ (SEQ ID NO: 551) TTR-489 Target:5′-GCATGCAGAGGTGGTATTCACAGCCAA-3′ (SEQ ID NO: 935)5′-AGAGGUGGUAUUCACAGCCAACGAC-3′ (SEQ ID NO: 1320)3′-CGUCUCCACCAUAAGUGUCGGUUGCUG-5′ (SEQ ID NO: 552) TTR-493 Target:5′-GCAGAGGTGGTATTCACAGCCAACGAC-3′ (SEQ ID NO: 936)5′-GAGGUGGUAUUCACAGCCAACGACU-3′ (SEQ ID NO: 1321)3′-GUCUCCACCAUAAGUGUCGGUUGCUGA-5′ (SEQ ID NO: 553) TTR-494 Target:5′-CAGAGGTGGTATTCACAGCCAACGACT-3′ (SEQ ID NO: 937)5′-GUCGUCACCAAUCCCAAGGAAUGAG-3′ (SEQ ID NO: 1322)3′-GACAGCAGUGGUUAGGGUUCCUUACUC-5′ (SEQ ID NO: 554) TTR-581 Target:5′-CTGTCGTCACCAATCCCAAGGAATGAG-3′ (SEQ ID NO: 938)5′-GGACGAGGGAUGGGAUUUCAUGUAA-3′ (SEQ ID NO: 1323)3′-UUCCUGCUCCCUACCCUAAAGUACAUU-5′ (SEQ ID NO: 555) TTR-631 Target:5′-AAGGACGAGGGATGGGATTTCATGTAA-3′ (SEQ ID NO: 939)5′-GACGAGGGAUGGGAUUUCAUGUAAC-3′ (SEQ ID NO: 1324)3′-UCCUGCUCCCUACCCUAAAGUACAUUG-5′ (SEQ ID NO: 556) TTR-632 Target:5′-AGGACGAGGGATGGGATTTCATGTAAC-3′ (SEQ ID NO: 940)5′-GAGGGAUGGGAUUUCAUGUAACCAA-3′ (SEQ ID NO: 1325)3′-UGCUCCCUACCCUAAAGUACAUUGGUU-5′ (SEQ ID NO: 557) TTR-635 Target:5′-ACGAGGGATGGGATTTCATGTAACCAA-3′ (SEQ ID NO: 941)5′-AGGGAUGGGAUUUCAUGUAACCAAG-3′ (SEQ ID NO: 1326)3′-GCUCCCUACCCUAAAGUACAUUGGUUC-5′ (SEQ ID NO: 558) TTR-636 Target:5′-CGAGGGATGGGATTTCATGTAACCAAG-3′ (SEQ ID NO: 942)5′-GGGAUGGGAUUUCAUGUAACCAAGA-3′ (SEQ ID NO: 1327)3′-CUCCCUACCCUAAAGUACAUUGGUUCU-5′ (SEQ ID NO: 559) TTR-637 Target:5′-GAGGGATGGGATTTCATGTAACCAAGA-3′ (SEQ ID NO: 943)5′-GAUGGGAUUUCAUGUAACCAAGAGU-3′ (SEQ ID NO: 1328)3′-CCCUACCCUAAAGUACAUUGGUUCUCA-5′ (SEQ ID NO: 560) TTR-639 Target:5′-GGGATGGGATTTCATGTAACCAAGAGT-3′ (SEQ ID NO: 944)5′-AUGGGAUUUCAUGUAACCAAGAGUA-3′ (SEQ ID NO: 1329)3′-CCUACCCUAAAGUACAUUGGUUCUCAU-5′ (SEQ ID NO: 561) TTR-640 Target:5′-GGATGGGATTTCATGTAACCAAGAGTA-3′ (SEQ ID NO: 945)5′-UGGGAUUUCAUGUAACCAAGAGUAU-3′ (SEQ ID NO: 1330)3′-CUACCCUAAAGUACAUUGGUUCUCAUA-5′ (SEQ ID NO: 562) TTR-641 Target:5′-GATGGGATTTCATGTAACCAAGAGTAT-3′ (SEQ ID NO: 946)5′-GGGAUUUCAUGUAACCAAGAGUAUU-3′ (SEQ ID NO: 1331)3′-UACCCUAAAGUACAUUGGUUCUCAUAA-5′ (SEQ ID NO: 563) TTR-642 Target:5′-ATGGGATTTCATGTAACCAAGAGTATT-3′ (SEQ ID NO: 947)5′-GGAUUUCAUGUAACCAAGAGUAUUC-3′ (SEQ ID NO: 1332)3′-ACCCUAAAGUACAUUGGUUCUCAUAAG-5′ (SEQ ID NO: 564) TTR-643 Target:5′-TGGGATTTCATGTAACCAAGAGTATTC-3′ (SEQ ID NO: 948)5′-GAUUUCAUGUAACCAAGAGUAUUCC-3′ (SEQ ID NO: 1333)3′-CCCUAAAGUACAUUGGUUCUCAUAAGG-5′ (SEQ ID NO: 565) TTR-644 Target:5′-GGGATTTCATGTAACCAAGAGTATTCC-3′ (SEQ ID NO: 949)5′-AUUUCAUGUAACCAAGAGUAUUCCA-3′ (SEQ ID NO: 1334)3′-CCUAAAGUACAUUGGUUCUCAUAAGGU-5′ (SEQ ID NO: 566) TTR-645 Target:5′-GGATTTCATGTAACCAAGAGTATTCCA-3′ (SEQ ID NO: 950)5′-UUUCAUGUAACCAAGAGUAUUCCAU-3′ (SEQ ID NO: 1335)3′-CUAAAGUACAUUGGUUCUCAUAAGGUA-5′ (SEQ ID NO: 567) TTR-646 Target:5′-GATTTCATGTAACCAAGAGTATTCCAT-3′ (SEQ ID NO: 951)5′-UUCAUGUAACCAAGAGUAUUCCAUU-3′ (SEQ ID NO: 1336)3′-UAAAGUACAUUGGUUCUCAUAAGGUAA-5′ (SEQ ID NO: 568) TTR-647 Target:5′-ATTTCATGTAACCAAGAGTATTCCATT-3′ (SEQ ID NO: 952)5′-UCAUGUAACCAAGAGUAUUCCAUUU-3′ (SEQ ID NO: 1337)3′-AAAGUACAUUGGUUCUCAUAAGGUAAA-5′ (SEQ ID NO: 569) TTR-648 Target:5′-TTTCATGTAACCAAGAGTATTCCATTT-3′ (SEQ ID NO: 953)5′-CAUGUAACCAAGAGUAUUCCAUUUU-3′ (SEQ ID NO: 1338)3′-AAGUACAUUGGUUCUCAUAAGGUAAAA-5′ (SEQ ID NO: 570) TTR-649 Target:5′-TTCATGTAACCAAGAGTATTCCATTTT-3′ (SEQ ID NO: 954)5′-AUGUAACCAAGAGUAUUCCAUUUUU-3′ (SEQ ID NO: 1339)3′-AGUACAUUGGUUCUCAUAAGGUAAAAA-5′ (SEQ ID NO: 571) TTR-650 Target:5′-TCATGTAACCAAGAGTATTCCATTTTT-3′ (SEQ ID NO: 955)5′-UGUAACCAAGAGUAUUCCAUUUUUA-3′ (SEQ ID NO: 1340)3′-GUACAUUGGUUCUCAUAAGGUAAAAAU-5′ (SEQ ID NO: 572) TTR-651 Target:5′-CATGTAACCAAGAGTATTCCATTTTTA-3′ (SEQ ID NO: 956)5′-GUAACCAAGAGUAUUCCAUUUUUAC-3′ (SEQ ID NO: 1341)3′-UACAUUGGUUCUCAUAAGGUAAAAAUG-5′ (SEQ ID NO: 573) TTR-652 Target:5′-ATGTAACCAAGAGTATTCCATTTTTAC-3′ (SEQ ID NO: 957)5′-UAACCAAGAGUAUUCCAUUUUUACU-3′ (SEQ ID NO: 1342)3′-ACAUUGGUUCUCAUAAGGUAAAAAUGA-5′ (SEQ ID NO: 574) TTR-653 Target:5′-TGTAACCAAGAGTATTCCATTTTTACT-3′ (SEQ ID NO: 958)5′-AACCAAGAGUAUUCCAUUUUUACUA-3′ (SEQ ID NO: 1343)3′-CAUUGGUUCUCAUAAGGUAAAAAUGAU-5′ (SEQ ID NO: 575) TTR-654 Target:5′-GTAACCAAGAGTATTCCATTTTTACTA-3′ (SEQ ID NO: 959)5′-ACCAAGAGUAUUCCAUUUUUACUAA-3′ (SEQ ID NO: 1344)3′-AUUGGUUCUCAUAAGGUAAAAAUGAUU-5′ (SEQ ID NO: 576) TTR-655 Target:5′-TAACCAAGAGTATTCCATTTTTACTAA-3′ (SEQ ID NO: 960)5′-CCAAGAGUAUUCCAUUUUUACUAAA-3′ (SEQ ID NO: 1345)3′-UUGGUUCUCAUAAGGUAAAAAUGAUUU-5′ (SEQ ID NO: 577) TTR-656 Target:5′-AACCAAGAGTATTCCATTTTTACTAAA-3′ (SEQ ID NO: 961)5′-CAAGAGUAUUCCAUUUUUACUAAAG-3′ (SEQ ID NO: 1346)3′-UGGUUCUCAUAAGGUAAAAAUGAUUUC-5′ (SEQ ID NO: 578) TTR-657 Target:5′-ACCAAGAGTATTCCATTTTTACTAAAG-3′ (SEQ ID NO: 962)5′-AAGAGUAUUCCAUUUUUACUAAAGC-3′ (SEQ ID NO: 1347)3′-GGUUCUCAUAAGGUAAAAAUGAUUUCG-5′ (SEQ ID NO: 579) TTR-658 Target:5′-CCAAGAGTATTCCATTTTTACTAAAGC-3′ (SEQ ID NO: 963)5′-AGAGUAUUCCAUUUUUACUAAAGCA-3′ (SEQ ID NO: 1348)3′-GUUCUCAUAAGGUAAAAAUGAUUUCGU-5′ (SEQ ID NO: 580) TTR-659 Target:5′-CAAGAGTATTCCATTTTTACTAAAGCA-3′ (SEQ ID NO: 964)5′-GAGUAUUCCAUUUUUACUAAAGCAG-3′ (SEQ ID NO: 1349)3′-UUCUCAUAAGGUAAAAAUGAUUUCGUC-5′ (SEQ ID NO: 581) TTR-660 Target:5′-AAGAGTATTCCATTTTTACTAAAGCAG-3′ (SEQ ID NO: 965)5′-AGUAUUCCAUUUUUACUAAAGCAGU-3′ (SEQ ID NO: 1350)3′-UCUCAUAAGGUAAAAAUGAUUUCGUCA-5′ (SEQ ID NO: 582) TTR-661 Target:5′-AGAGTATTCCATTTTTACTAAAGCAGT-3′ (SEQ ID NO: 966)5′-GUAUUCCAUUUUUACUAAAGCAGUG-3′ (SEQ ID NO: 1351)3′-CUCAUAAGGUAAAAAUGAUUUCGUCAC-5′ (SEQ ID NO: 583) TTR-662 Target:5′-GAGTATTCCATTTTTACTAAAGCAGTG-3′ (SEQ ID NO: 967)5′-UAUUCCAUUUUUACUAAAGCAGUGU-3′ (SEQ ID NO: 1352)3′-UCAUAAGGUAAAAAUGAUUUCGUCACA-5′ (SEQ ID NO: 584) TTR-663 Target:5′-AGTATTCCATTTTTACTAAAGCAGTGT-3′ (SEQ ID NO: 968)5′-AUUCCAUUUUUACUAAAGCAGUGUU-3′ (SEQ ID NO: 1353)3′-CAUAAGGUAAAAAUGAUUUCGUCACAA-5′ (SEQ ID NO: 585) TTR-664 Target:5′-GTATTCCATTTTTACTAAAGCAGTGTT-3′ (SEQ ID NO: 969)5′-UUCCAUUUUUACUAAAGCAGUGUUU-3′ (SEQ ID NO: 1354)3′-AUAAGGUAAAAAUGAUUUCGUCACAAA-5′ (SEQ ID NO: 586) TTR-665 Target:5′-TATTCCATTTTTACTAAAGCAGTGTTT-3′ (SEQ ID NO: 970)5′-UCCAUUUUUACUAAAGCAGUGUUUU-3′ (SEQ ID NO: 1355)3′-UAAGGUAAAAAUGAUUUCGUCACAAAA-5′ (SEQ ID NO: 587) TTR-666 Target:5′-ATTCCATTTTTACTAAAGCAGTGTTTT-3′ (SEQ ID NO: 971)5′-CCAUUUUUACUAAAGCAGUGUUUUC-3′ (SEQ ID NO: 1356)3′-AAGGUAAAAAUGAUUUCGUCACAAAAG-5′ (SEQ ID NO: 588) TTR-667 Target:5′-TTCCATTTTTACTAAAGCAGTGTTTTC-3′ (SEQ ID NO: 972)5′-CAUUUUUACUAAAGCAGUGUUUUCA-3′ (SEQ ID NO: 1357)3′-AGGUAAAAAUGAUUUCGUCACAAAAGU-5′ (SEQ ID NO: 589) TTR-668 Target:5′-TCCATTTTTACTAAAGCAGTGTTTTCA-3′ (SEQ ID NO: 973)5′-AUUUUUACUAAAGCAGUGUUUUCAC-3′ (SEQ ID NO: 1358)3′-GGUAAAAAUGAUUUCGUCACAAAAGUG-5′ (SEQ ID NO: 590) TTR-669 Target:5′-CCATTTTTACTAAAGCAGTGTTTTCAC-3′ (SEQ ID NO: 974)5′-UUUUUACUAAAGCAGUGUUUUCACC-3′ (SEQ ID NO: 1359)3′-GUAAAAAUGAUUUCGUCACAAAAGUGG-5′ (SEQ ID NO: 591) TTR-670 Target:5′-CATTTTTACTAAAGCAGTGTTTTCACC-3′ (SEQ ID NO: 975)5′-UUUUACUAAAGCAGUGUUUUCACCU-3′ (SEQ ID NO: 1360)3′-UAAAAAUGAUUUCGUCACAAAAGUGGA-5′ (SEQ ID NO: 592) TTR-671 Target:5′-ATTTTTACTAAAGCAGTGTTTTCACCT-3′ (SEQ ID NO: 976)5′-UUUACUAAAGCAGUGUUUUCACCUC-3′ (SEQ ID NO: 1361)3′-AAAAAUGAUUUCGUCACAAAAGUGGAG-5′ (SEQ ID NO: 593) TTR-672 Target:5′-TTTTTACTAAAGCAGTGTTTTCACCTC-3′ (SEQ ID NO: 977)5′-UUACUAAAGCAGUGUUUUCACCUCA-3′ (SEQ ID NO: 1362)3′-AAAAUGAUUUCGUCACAAAAGUGGAGU-5′ (SEQ ID NO: 594) TTR-673 Target:5′-TTTTACTAAAGCAGTGTTTTCACCTCA-3′ (SEQ ID NO: 978)5′-UACUAAAGCAGUGUUUUCACCUCAU-3′ (SEQ ID NO: 1363)3′-AAAUGAUUUCGUCACAAAAGUGGAGUA-5′ (SEQ ID NO: 595) TTR-674 Target:5′-TTTACTAAAGCAGTGTTTTCACCTCAT-3′ (SEQ ID NO: 979)5′-ACUAAAGCAGUGUUUUCACCUCAUA-3′ (SEQ ID NO: 1364)3′-AAUGAUUUCGUCACAAAAGUGGAGUAU-5′ (SEQ ID NO: 596) TTR-675 Target:5′-TTACTAAAGCAGTGTTTTCACCTCATA-3′ (SEQ ID NO: 980)5′-CUAAAGCAGUGUUUUCACCUCAUAU-3′ (SEQ ID NO: 1365)3′-AUGAUUUCGUCACAAAAGUGGAGUAUA-5′ (SEQ ID NO: 597) TTR-676 Target:5′-TACTAAAGCAGTGTTTTCACCTCATAT-3′ (SEQ ID NO: 981)5′-UAAAGCAGUGUUUUCACCUCAUAUG-3′ (SEQ ID NO: 1366)3′-UGAUUUCGUCACAAAAGUGGAGUAUAC-5′ (SEQ ID NO: 598) TTR-677 Target:5′-ACTAAAGCAGTGTTTTCACCTCATATG-3′ (SEQ ID NO: 982)5′-AAAGCAGUGUUUUCACCUCAUAUGC-3′ (SEQ ID NO: 1367)3′-GAUUUCGUCACAAAAGUGGAGUAUACG-5′ (SEQ ID NO: 599) TTR-678 Target:5′-CTAAAGCAGTGTTTTCACCTCATATGC-3′ (SEQ ID NO: 983)5′-AAGCAGUGUUUUCACCUCAUAUGCU-3′ (SEQ ID NO: 1368)3′-AUUUCGUCACAAAAGUGGAGUAUACGA-5′ (SEQ ID NO: 600) TTR-679 Target:5′-TAAAGCAGTGTTTTCACCTCATATGCT-3′ (SEQ ID NO: 984)5′-AGCAGUGUUUUCACCUCAUAUGCUA-3′ (SEQ ID NO: 1369)3′-UUUCGUCACAAAAGUGGAGUAUACGAU-5′ (SEQ ID NO: 601) TTR-680 Target:5′-AAAGCAGTGTTTTCACCTCATATGCTA-3′ (SEQ ID NO: 985)5′-GCAGUGUUUUCACCUCAUAUGCUAU-3′ (SEQ ID NO: 1370)3′-UUCGUCACAAAAGUGGAGUAUACGAUA-5′ (SEQ ID NO: 602) TTR-681 Target:5′-AAGCAGTGTTTTCACCTCATATGCTAT-3′ (SEQ ID NO: 986)5′-CAGUGUUUUCACCUCAUAUGCUAUG-3′ (SEQ ID NO: 1371)3′-UCGUCACAAAAGUGGAGUAUACGAUAC-5′ (SEQ ID NO: 603) TTR-682 Target:5′-AGCAGTGTTTTCACCTCATATGCTATG-3′ (SEQ ID NO: 987)5′-AGUGUUUUCACCUCAUAUGCUAUGU-3′ (SEQ ID NO: 1372)3′-CGUCACAAAAGUGGAGUAUACGAUACA-5′ (SEQ ID NO: 604) TTR-683 Target:5′-GCAGTGTTTTCACCTCATATGCTATGT-3′ (SEQ ID NO: 988)5′-GUGUUUUCACCUCAUAUGCUAUGUU-3′ (SEQ ID NO: 1373)3′-GUCACAAAAGUGGAGUAUACGAUACAA-5′ (SEQ ID NO: 605) TTR-684 Target:5′-CAGTGTTTTCACCTCATATGCTATGTT-3′ (SEQ ID NO: 989)5′-UGUUUUCACCUCAUAUGCUAUGUUA-3′ (SEQ ID NO: 1374)3′-UCACAAAAGUGGAGUAUACGAUACAAU-5′ (SEQ ID NO: 606) TTR-685 Target:5′-AGTGTTTTCACCTCATATGCTATGTTA-3′ (SEQ ID NO: 990)5′-GUUUUCACCUCAUAUGCUAUGUUAG-3′ (SEQ ID NO: 1375)3′-CACAAAAGUGGAGUAUACGAUACAAUC-5′ (SEQ ID NO: 607) TTR-686 Target:5′-GTGTTTTCACCTCATATGCTATGTTAG-3′ (SEQ ID NO: 991)5′-UUUUCACCUCAUAUGCUAUGUUAGA-3′ (SEQ ID NO: 1376)3′-ACAAAAGUGGAGUAUACGAUACAAUCU-5′ (SEQ ID NO: 608) TTR-687 Target:5′-TGTTTTCACCTCATATGCTATGTTAGA-3′ (SEQ ID NO: 992)5′-UUUCACCUCAUAUGCUAUGUUAGAA-3′ (SEQ ID NO: 1377)3′-CAAAAGUGGAGUAUACGAUACAAUCUU-5′ (SEQ ID NO: 609) TTR-688 Target:5′-GTTTTCACCTCATATGCTATGTTAGAA-3′ (SEQ ID NO: 993)5′-UUCACCUCAUAUGCUAUGUUAGAAG-3′ (SEQ ID NO: 1378)3′-AAAAGUGGAGUAUACGAUACAAUCUUC-5′ (SEQ ID NO: 610) TTR-689 Target:5′-TTTTCACCTCATATGCTATGTTAGAAG-3′ (SEQ ID NO: 994)5′-UCACCUCAUAUGCUAUGUUAGAAGU-3′ (SEQ ID NO: 1379)3′-AAAGUGGAGUAUACGAUACAAUCUUCA-5′ (SEQ ID NO: 611) TTR-690 Target:5′-TTTCACCTCATATGCTATGTTAGAAGT-3′ (SEQ ID NO: 995)5′-CACCUCAUAUGCUAUGUUAGAAGUC-3′ (SEQ ID NO: 1380)3′-AAGUGGAGUAUACGAUACAAUCUUCAG-5′ (SEQ ID NO: 612) TTR-691 Target:5′-TTCACCTCATATGCTATGTTAGAAGTC-3′ (SEQ ID NO: 996)5′-ACCUCAUAUGCUAUGUUAGAAGUCC-3′ (SEQ ID NO: 1381)3′-AGUGGAGUAUACGAUACAAUCUUCAGG-5′ (SEQ ID NO: 613) TTR-692 Target:5′-TCACCTCATATGCTATGTTAGAAGTCC-3′ (SEQ ID NO: 997)5′-CCUCAUAUGCUAUGUUAGAAGUCCA-3′ (SEQ ID NO: 1382)3′-GUGGAGUAUACGAUACAAUCUUCAGGU-5′ (SEQ ID NO: 614) TTR-693 Target:5′-CACCTCATATGCTATGTTAGAAGTCCA-3′ (SEQ ID NO: 998)5′-CUCAUAUGCUAUGUUAGAAGUCCAG-3′ (SEQ ID NO: 1383)3′-UGGAGUAUACGAUACAAUCUUCAGGUC-5′ (SEQ ID NO: 615) TTR-694 Target:5′-ACCTCATATGCTATGTTAGAAGTCCAG-3′ (SEQ ID NO: 999)5′-UCAUAUGCUAUGUUAGAAGUCCAGG-3′ (SEQ ID NO: 1384)3′-GGAGUAUACGAUACAAUCUUCAGGUCC-5′ (SEQ ID NO: 616) TTR-695 Target:5′-CCTCATATGCTATGTTAGAAGTCCAGG-3′ (SEQ ID NO: 1000)5′-CAUAUGCUAUGUUAGAAGUCCAGGC-3′ (SEQ ID NO: 1385)3′-GAGUAUACGAUACAAUCUUCAGGUCCG-5′ (SEQ ID NO: 617) TTR-696 Target:5′-CTCATATGCTATGTTAGAAGTCCAGGC-3′ (SEQ ID NO: 1001)5′-AUAUGCUAUGUUAGAAGUCCAGGCA-3′ (SEQ ID NO: 1386)3′-AGUAUACGAUACAAUCUUCAGGUCCGU-5′ (SEQ ID NO: 618) TTR-697 Target:5′-TCATATGCTATGTTAGAAGTCCAGGCA-3′ (SEQ ID NO: 1002)5′-UAUGCUAUGUUAGAAGUCCAGGCAG-3′ (SEQ ID NO: 1387)3′-GUAUACGAUACAAUCUUCAGGUCCGUC-5′ (SEQ ID NO: 619) TTR-698 Target:5′-CATATGCTATGTTAGAAGTCCAGGCAG-3′ (SEQ ID NO: 1003)5′-AUGCUAUGUUAGAAGUCCAGGCAGA-3′ (SEQ ID NO: 1388)3′-UAUACGAUACAAUCUUCAGGUCCGUCU-5′ (SEQ ID NO: 620) TTR-699 Target:5′-ATATGCTATGTTAGAAGTCCAGGCAGA-3′ (SEQ ID NO: 1004)5′-CUAUGUUAGAAGUCCAGGCAGAGAC-3′ (SEQ ID NO: 1389)3′-ACGAUACAAUCUUCAGGUCCGUCUCUG-5′ (SEQ ID NO: 621) TTR-702 Target:5′-TGCTATGTTAGAAGTCCAGGCAGAGAC-3′ (SEQ ID NO: 1005)5′-AUGUUAGAAGUCCAGGCAGAGACAA-3′ (SEQ ID NO: 1390)3′-GAUACAAUCUUCAGGUCCGUCUCUGUU-5′ (SEQ ID NO: 622) TTR-704 Target:5′-CTATGTTAGAAGTCCAGGCAGAGACAA-3′ (SEQ ID NO: 1006)5′-UGUUAGAAGUCCAGGCAGAGACAAU-3′ (SEQ ID NO: 1391)3′-AUACAAUCUUCAGGUCCGUCUCUGUUA-5′ (SEQ ID NO: 623) TTR-705 Target:5′-TATGTTAGAAGTCCAGGCAGAGACAAT-3′ (SEQ ID NO: 1007)5′-GUUAGAAGUCCAGGCAGAGACAAUA-3′ (SEQ ID NO: 1392)3′-UACAAUCUUCAGGUCCGUCUCUGUUAU-5′ (SEQ ID NO: 624) TTR-706 Target:5′-ATGTTAGAAGTCCAGGCAGAGACAATA-3′ (SEQ ID NO: 1008)5′-UUAGAAGUCCAGGCAGAGACAAUAA-3′ (SEQ ID NO: 1393)3′-ACAAUCUUCAGGUCCGUCUCUGUUAUU-5′ (SEQ ID NO: 625) TTR-707 Target:5′-TGTTAGAAGTCCAGGCAGAGACAATAA-3′ (SEQ ID NO: 1009)5′-UAGAAGUCCAGGCAGAGACAAUAAA-3′ (SEQ ID NO: 1394)3′-CAAUCUUCAGGUCCGUCUCUGUUAUUU-5′ (SEQ ID NO: 626) TTR-708 Target:5′-GTTAGAAGTCCAGGCAGAGACAATAAA-3′ (SEQ ID NO: 1010)5′-AGAAGUCCAGGCAGAGACAAUAAAA-3′ (SEQ ID NO: 1395)3′-AAUCUUCAGGUCCGUCUCUGUUAUUUU-5′ (SEQ ID NO: 627) TTR-709 Target:5′-TTAGAAGTCCAGGCAGAGACAATAAAA-3′ (SEQ ID NO: 1011)5′-GAAGUCCAGGCAGAGACAAUAAAAC-3′ (SEQ ID NO: 1396)3′-AUCUUCAGGUCCGUCUCUGUUAUUUUG-5′ (SEQ ID NO: 628) TTR-710 Target:5′-TAGAAGTCCAGGCAGAGACAATAAAAC-3′ (SEQ ID NO: 1012)5′-AAGUCCAGGCAGAGACAAUAAAACA-3′ (SEQ ID NO: 1397)3′-UCUUCAGGUCCGUCUCUGUUAUUUUGU-5′ (SEQ ID NO: 629) TTR-711 Target:5′-AGAAGTCCAGGCAGAGACAATAAAACA-3′ (SEQ ID NO: 1013)5′-AGUCCAGGCAGAGACAAUAAAACAU-3′ (SEQ ID NO: 1398)3′-CUUCAGGUCCGUCUCUGUUAUUUUGUA-5′ (SEQ ID NO: 630) TTR-712 Target:5′-GAAGTCCAGGCAGAGACAATAAAACAT-3′ (SEQ ID NO: 1014)5′-GUCCAGGCAGAGACAAUAAAACAUU-3′ (SEQ ID NO: 1399)3′-UUCAGGUCCGUCUCUGUUAUUUUGUAA-5′ (SEQ ID NO: 631) TTR-713 Target:5′-AAGTCCAGGCAGAGACAATAAAACATT-3′ (SEQ ID NO: 1015)5′-UCCAGGCAGAGACAAUAAAACAUUC-3′ (SEQ ID NO: 1400)3′-UCAGGUCCGUCUCUGUUAUUUUGUAAG-5′ (SEQ ID NO: 632) TTR-714 Target:5′-AGTCCAGGCAGAGACAATAAAACATTC-3′ (SEQ ID NO: 1016)5′-CAGGCAGAGACAAUAAAACAUUCCU-3′ (SEQ ID NO: 1401)3′-AGGUCCGUCUCUGUUAUUUUGUAAGGA-5′ (SEQ ID NO: 633) TTR-716 Target:5′-TCCAGGCAGAGACAATAAAACATTCCT-3′ (SEQ ID NO: 1017)5′-AGGCAGAGACAAUAAAACAUUCCUG-3′ (SEQ ID NO: 1402)3′-GGUCCGUCUCUGUUAUUUUGUAAGGAC-5′ (SEQ ID NO: 634) TTR-717 Target:5′-CCAGGCAGAGACAATAAAACATTCCTG-3′ (SEQ ID NO: 1018)5′-GGCAGAGACAAUAAAACAUUCCUGU-3′ (SEQ ID NO: 1403)3′-GUCCGUCUCUGUUAUUUUGUAAGGACA-5′ (SEQ ID NO: 635) TTR-718 Target:5′-CAGGCAGAGACAATAAAACATTCCTGT-3′ (SEQ ID NO: 1019)5′-GCAGAGACAAUAAAACAUUCCUGUG-3′ (SEQ ID NO: 1404)3′-UCCGUCUCUGUUAUUUUGUAAGGACAC-5′ (SEQ ID NO: 636) TTR-719 Target:5′-AGGCAGAGACAATAAAACATTCCTGTG-3′ (SEQ ID NO: 1020)5′-CAGAGACAAUAAAACAUUCCUGUGA-3′ (SEQ ID NO: 1405)3′-CCGUCUCUGUUAUUUUGUAAGGACACU-5′ (SEQ ID NO: 637) TTR-720 Target:5′-GGCAGAGACAATAAAACATTCCTGTGA-3′ (SEQ ID NO: 1021)5′-AGAGACAAUAAAACAUUCCUGUGAA-3′ (SEQ ID NO: 1406)3′-CGUCUCUGUUAUUUUGUAAGGACACUU-5′ (SEQ ID NO: 638) TTR-721 Target:5′-GCAGAGACAATAAAACATTCCTGTGAA-3′ (SEQ ID NO: 1022)5′-GAGACAAUAAAACAUUCCUGUGAAA-3′ (SEQ ID NO: 1407)3′-GUCUCUGUUAUUUUGUAAGGACACUUU-5′ (SEQ ID NO: 639) TTR-722 Target:5′-CAGAGACAATAAAACATTCCTGTGAAA-3′ (SEQ ID NO: 1023)5′-AGACAAUAAAACAUUCCUGUGAAAG-3′ (SEQ ID NO: 1408)3′-UCUCUGUUAUUUUGUAAGGACACUUUC-5′ (SEQ ID NO: 640) TTR-723 Target:5′-AGAGACAATAAAACATTCCTGTGAAAG-3′ (SEQ ID NO: 1024)5′-GACAAUAAAACAUUCCUGUGAAAGG-3′ (SEQ ID NO: 1409)3′-CUCUGUUAUUUUGUAAGGACACUUUCC-5′ (SEQ ID NO: 641) TTR-724 Target:5′-GAGACAATAAAACATTCCTGTGAAAGG-3′ (SEQ ID NO: 1025)5′-ACAAUAAAACAUUCCUGUGAAAGGC-3′ (SEQ ID NO: 1410)3′-UCUGUUAUUUUGUAAGGACACUUUCCG-5′ (SEQ ID NO: 642) TTR-725 Target:5′-AGACAATAAAACATTCCTGTGAAAGGC-3′ (SEQ ID NO: 1026)5′-CAAUAAAACAUUCCUGUGAAAGGCA-3′ (SEQ ID NO: 1411)3′-CUGUUAUUUUGUAAGGACACUUUCCGU-5′ (SEQ ID NO: 643) TTR-726 Target:5′-GACAATAAAACATTCCTGTGAAAGGCA-3′ (SEQ ID NO: 1027)5′-AAUAAAACAUUCCUGUGAAAGGCAC-3′ (SEQ ID NO: 1412)3′-UGUUAUUUUGUAAGGACACUUUCCGUG-5′ (SEQ ID NO: 644) TTR-727 Target:5′-ACAATAAAACATTCCTGTGAAAGGCAC-3′ (SEQ ID NO: 1028)5′-AUAAAACAUUCCUGUGAAAGGCACU-3′ (SEQ ID NO: 1413)3′-GUUAUUUUGUAAGGACACUUUCCGUGA-5′ (SEQ ID NO: 645) TTR-728 Target:5′-CAATAAAACATTCCTGTGAAAGGCACT-3′ (SEQ ID NO: 1029)5′-AAACAUUCCUGUGAAAGGCACUUUU-3′ (SEQ ID NO: 1414)3′-AUUUUGUAAGGACACUUUCCGUGAAAA-5′ (SEQ ID NO: 646) TTR-731 Target:5′-TAAAACATTCCTGTGAAAGGCACTTTT-3′ (SEQ ID NO: 1030)5′-AACAUUCCUGUGAAAGGCACUUUUC-3′ (SEQ ID NO: 1415)3′-UUUUGUAAGGACACUUUCCGUGAAAAG-5′ (SEQ ID NO: 647) TTR-732 Target:5′-AAAACATTCCTGTGAAAGGCACTTTTC-3′ (SEQ ID NO: 1031)5′-ACAUUCCUGUGAAAGGCACUUUUCA-3′ (SEQ ID NO: 1416)3′-UUUGUAAGGACACUUUCCGUGAAAAGU-5′ (SEQ ID NO: 648) TTR-733 Target:5′-AAACATTCCTGTGAAAGGCACTTTTCA-3′ (SEQ ID NO: 1032)5′-CAUUCCUGUGAAAGGCACUUUUCAU-3′ (SEQ ID NO: 1417)3′-UUGUAAGGACACUUUCCGUGAAAAGUA-5′ (SEQ ID NO: 649) TTR-734 Target:5′-AACATTCCTGTGAAAGGCACTTTTCAT-3′ (SEQ ID NO: 1033)5′-AUUCCUGUGAAAGGCACUUUUCAUU-3′ (SEQ ID NO: 1418)3′-UGUAAGGACACUUUCCGUGAAAAGUAA-5′ (SEQ ID NO: 650) TTR-735 Target:5′-ACATTCCTGTGAAAGGCACTTTTCATT-3′ (SEQ ID NO: 1034)5′-UUCCUGUGAAAGGCACUUUUCAUUC-3′ (SEQ ID NO: 1419)3′-GUAAGGACACUUUCCGUGAAAAGUAAG-5′ (SEQ ID NO: 651) TTR-736 Target:5′-CATTCCTGTGAAAGGCACTTTTCATTC-3′ (SEQ ID NO: 1035)5′-CCUGUGAAAGGCACUUUUCAUUCCA-3′ (SEQ ID NO: 1420)3′-AAGGACACUUUCCGUGAAAAGUAAGGU-5′ (SEQ ID NO: 652) TTR-738 Target:5′-TTCCTGTGAAAGGCACTTTTCATTCCA-3′ (SEQ ID NO: 1036)5′-CUGUGAAAGGCACUUUUCAUUCCAC-3′ (SEQ ID NO: 1421)3′-AGGACACUUUCCGUGAAAAGUAAGGUG-5′ (SEQ ID NO: 653) TTR-739 Target:5′-TCCTGTGAAAGGCACTTTTCATTCCAC-3′ (SEQ ID NO: 1037)5′-UGUGAAAGGCACUUUUCAUUCCACU-3′ (SEQ ID NO: 1422)3′-GGACACUUUCCGUGAAAAGUAAGGUGA-5′ (SEQ ID NO: 654) TTR-740 Target:5′-CCTGTGAAAGGCACTTTTCATTCCACT-3′ (SEQ ID NO: 1038)5′-GUGAAAGGCACUUUUCAUUCCACUU-3′ (SEQ ID NO: 1423)3′-GACACUUUCCGUGAAAAGUAAGGUGAA-5′ (SEQ ID NO: 655) TTR-741 Target:5′-CTGTGAAAGGCACTTTTCATTCCACTT-3′ (SEQ ID NO: 1039)5′-UGAAAGGCACUUUUCAUUCCACUUU-3′ (SEQ ID NO: 1424)3′-ACACUUUCCGUGAAAAGUAAGGUGAAA-5′ (SEQ ID NO: 656) TTR-742 Target:5′-TGTGAAAGGCACTTTTCATTCCACTTT-3′ (SEQ ID NO: 1040)5′-GAAAGGCACUUUUCAUUCCACUUUA-3′ (SEQ ID NO: 1425)3′-CACUUUCCGUGAAAAGUAAGGUGAAAU-5′ (SEQ ID NO: 657) TTR-743 Target:5′-GTGAAAGGCACTTTTCATTCCACTTTA-3′ (SEQ ID NO: 1041)5′-AAAGGCACUUUUCAUUCCACUUUAA-3′ (SEQ ID NO: 1426)3′-ACUUUCCGUGAAAAGUAAGGUGAAAUU-5′ (SEQ ID NO: 658) TTR-744 Target:5′-TGAAAGGCACTTTTCATTCCACTTTAA-3′ (SEQ ID NO: 1042)5′-AAGGCACUUUUCAUUCCACUUUAAC-3′ (SEQ ID NO: 1427)3′-CUUUCCGUGAAAAGUAAGGUGAAAUUG-5′ (SEQ ID NO: 659) TTR-745 Target:5′-GAAAGGCACTTTTCATTCCACTTTAAC-3′ (SEQ ID NO: 1043)5′-AGGCACUUUUCAUUCCACUUUAACU-3′ (SEQ ID NO: 1428)3′-UUUCCGUGAAAAGUAAGGUGAAAUUGA-5′ (SEQ ID NO: 660) TTR-746 Target:5′-AAAGGCACTTTTCATTCCACTTTAACT-3′ (SEQ ID NO: 1044)5′-GGCACUUUUCAUUCCACUUUAACUU-3′ (SEQ ID NO: 1429)3′-UUCCGUGAAAAGUAAGGUGAAAUUGAA-5′ (SEQ ID NO: 661) TTR-747 Target:5′-AAGGCACTTTTCATTCCACTTTAACTT-3′ (SEQ ID NO: 1045)5′-GCACUUUUCAUUCCACUUUAACUUG-3′ (SEQ ID NO: 1430)3′-UCCGUGAAAAGUAAGGUGAAAUUGAAC-5′ (SEQ ID NO: 662) TTR-748 Target:5′-AGGCACTTTTCATTCCACTTTAACTTG-3′ (SEQ ID NO: 1046)5′-CACUUUUCAUUCCACUUUAACUUGA-3′ (SEQ ID NO: 1431)3′-CCGUGAAAAGUAAGGUGAAAUUGAACU-5′ (SEQ ID NO: 663) TTR-749 Target:5′-GGCACTTTTCATTCCACTTTAACTTGA-3′ (SEQ ID NO: 1047)5′-ACUUUUCAUUCCACUUUAACUUGAU-3′ (SEQ ID NO: 1432)3′-CGUGAAAAGUAAGGUGAAAUUGAACUA-5′ (SEQ ID NO: 664) TTR-750 Target:5′-GCACTTTTCATTCCACTTTAACTTGAT-3′ (SEQ ID NO: 1048)5′-CUUUUCAUUCCACUUUAACUUGAUU-3′ (SEQ ID NO: 1433)3′-GUGAAAAGUAAGGUGAAAUUGAACUAA-5′ (SEQ ID NO: 665) TTR-751 Target:5′-CACTTTTCATTCCACTTTAACTTGATT-3′ (SEQ ID NO: 1049)5′-UUUUCAUUCCACUUUAACUUGAUUU-3′ (SEQ ID NO: 1434)3′-UGAAAAGUAAGGUGAAAUUGAACUAAA-5′ (SEQ ID NO: 666) TTR-752 Target:5′-ACTTTTCATTCCACTTTAACTTGATTT-3′ (SEQ ID NO: 1050)5′-UUUCAUUCCACUUUAACUUGAUUUU-3′ (SEQ ID NO: 1435)3′-GAAAAGUAAGGUGAAAUUGAACUAAAA-5′ (SEQ ID NO: 667) TTR-753 Target:5′-CTTTTCATTCCACTTTAACTTGATTTT-3′ (SEQ ID NO: 1051)5′-UUCAUUCCACUUUAACUUGAUUUUU-3′ (SEQ ID NO: 1436)3′-AAAAGUAAGGUGAAAUUGAACUAAAAA-5′ (SEQ ID NO: 668) TTR-754 Target:5′-TTTTCATTCCACTTTAACTTGATTTTT-3′ (SEQ ID NO: 1052)5′-UCAUUCCACUUUAACUUGAUUUUUU-3′ (SEQ ID NO: 1437)3′-AAAGUAAGGUGAAAUUGAACUAAAAAA-5′ (SEQ ID NO: 669) TTR-755 Target:5′-TTTCATTCCACTTTAACTTGATTTTTT-3′ (SEQ ID NO: 1053)5′-CAUUCCACUUUAACUUGAUUUUUUA-3′ (SEQ ID NO: 1438)3′-AAGUAAGGUGAAAUUGAACUAAAAAAU-5′ (SEQ ID NO: 670) TTR-756 Target:5′-TTCATTCCACTTTAACTTGATTTTTTA-3′ (SEQ ID NO: 1054)5′-AUUCCACUUUAACUUGAUUUUUUAA-3′ (SEQ ID NO: 1439)3′-AGUAAGGUGAAAUUGAACUAAAAAAUU-5′ (SEQ ID NO: 671) TTR-757 Target:5′-TCATTCCACTTTAACTTGATTTTTTAA-3′ (SEQ ID NO: 1055)5′-UUCCACUUUAACUUGAUUUUUUAAA-3′ (SEQ ID NO: 1440)3′-GUAAGGUGAAAUUGAACUAAAAAAUUU-5′ (SEQ ID NO: 672) TTR-758 Target:5′-CATTCCACTTTAACTTGATTTTTTAAA-3′ (SEQ ID NO: 1056)5′-UCCACUUUAACUUGAUUUUUUAAAU-3′ (SEQ ID NO: 1441)3′-UAAGGUGAAAUUGAACUAAAAAAUUUA-5′ (SEQ ID NO: 673) TTR-759 Target:5′-ATTCCACTTTAACTTGATTTTTTAAAT-3′ (SEQ ID NO: 1057)5′-CCACUUUAACUUGAUUUUUUAAAUU-3′ (SEQ ID NO: 1442)3′-AAGGUGAAAUUGAACUAAAAAAUUUAA-5′ (SEQ ID NO: 674) TTR-760 Target:5′-TTCCACTTTAACTTGATTTTTTAAATT-3′ (SEQ ID NO: 1058)5′-CACUUUAACUUGAUUUUUUAAAUUC-3′ (SEQ ID NO: 1443)3′-AGGUGAAAUUGAACUAAAAAAUUUAAG-5′ (SEQ ID NO: 675) TTR-761 Target:5′-TCCACTTTAACTTGATTTTTTAAATTC-3′ (SEQ ID NO: 1059)5′-ACUUUAACUUGAUUUUUUAAAUUCC-3′ (SEQ ID NO: 1444)3′-GGUGAAAUUGAACUAAAAAAUUUAAGG-5′ (SEQ ID NO: 676) TTR-762 Target:5′-CCACTTTAACTTGATTTTTTAAATTCC-3′ (SEQ ID NO: 1060)5′-CUUUAACUUGAUUUUUUAAAUUCCC-3′ (SEQ ID NO: 1445)3′-GUGAAAUUGAACUAAAAAAUUUAAGGG-5′ (SEQ ID NO: 677) TTR-763 Target:5′-CACTTTAACTTGATTTTTTAAATTCCC-3′ (SEQ ID NO: 1061)5′-UUUAACUUGAUUUUUUAAAUUCCCU-3′ (SEQ ID NO: 1446)3′-UGAAAUUGAACUAAAAAAUUUAAGGGA-5′ (SEQ ID NO: 678) TTR-764 Target:5′-ACTTTAACTTGATTTTTTAAATTCCCT-3′ (SEQ ID NO: 1062)5′-UUAACUUGAUUUUUUAAAUUCCCUU-3′ (SEQ ID NO: 1447)3′-GAAAUUGAACUAAAAAAUUUAAGGGAA-5′ (SEQ ID NO: 679) TTR-765 Target:5′-CTTTAACTTGATTTTTTAAATTCCCTT-3′ (SEQ ID NO: 1063)5′-UAACUUGAUUUUUUAAAUUCCCUUA-3′ (SEQ ID NO: 1448)3′-AAAUUGAACUAAAAAAUUUAAGGGAAU-5′ (SEQ ID NO: 680) TTR-766 Target:5′-TTTAACTTGATTTTTTAAATTCCCTTA-3′ (SEQ ID NO: 1064)5′-AACUUGAUUUUUUAAAUUCCCUUAU-3′ (SEQ ID NO: 1449)3′-AAUUGAACUAAAAAAUUUAAGGGAAUA-5′ (SEQ ID NO: 681) TTR-767 Target:5′-TTAACTTGATTTTTTAAATTCCCTTAT-3′ (SEQ ID NO: 1065)5′-ACUUGAUUUUUUAAAUUCCCUUAUU-3′ (SEQ ID NO: 1450)3′-AUUGAACUAAAAAAUUUAAGGGAAUAA-5′ (SEQ ID NO: 682) TTR-768 Target:5′-TAACTTGATTTTTTAAATTCCCTTATT-3′ (SEQ ID NO: 1066)5′-CUUGAUUUUUUAAAUUCCCUUAUUG-3′ (SEQ ID NO: 1451)3′-UUGAACUAAAAAAUUUAAGGGAAUAAC-5′ (SEQ ID NO: 683) TTR-769 Target:5′-AACTTGATTTTTTAAATTCCCTTATTG-3′ (SEQ ID NO: 1067)5′-UUGAUUUUUUAAAUUCCCUUAUUGU-3′ (SEQ ID NO: 1452)3′-UGAACUAAAAAAUUUAAGGGAAUAACA-5′ (SEQ ID NO: 684) TTR-770 Target:5′-ACTTGATTTTTTAAATTCCCTTATTGT-3′ (SEQ ID NO: 1068)5′-UGAUUUUUUAAAUUCCCUUAUUGUC-3′ (SEQ ID NO: 1453)3′-GAACUAAAAAAUUUAAGGGAAUAACAG-5′ (SEQ ID NO: 685) TTR-771 Target:5′-CTTGATTTTTTAAATTCCCTTATTGTC-3′ (SEQ ID NO: 1069)5′-GAUUUUUUAAAUUCCCUUAUUGUCC-3′ (SEQ ID NO: 1454)3′-AACUAAAAAAUUUAAGGGAAUAACAGG-5′ (SEQ ID NO: 686) TTR-772 Target:5′-TTGATTTTTTAAATTCCCTTATTGTCC-3′ (SEQ ID NO: 1070)5′-AUUUUUUAAAUUCCCUUAUUGUCCC-3′ (SEQ ID NO: 1455)3′-ACUAAAAAAUUUAAGGGAAUAACAGGG-5′ (SEQ ID NO: 687) TTR-773 Target:5′-TGATTTTTTAAATTCCCTTATTGTCCC-3′ (SEQ ID NO: 1071)5′-UUUUUAAAUUCCCUUAUUGUCCCUU-3′ (SEQ ID NO: 1456)3′-UAAAAAAUUUAAGGGAAUAACAGGGAA-5′ (SEQ ID NO: 688) TTR-775 Target:5′-ATTTTTTAAATTCCCTTATTGTCCCTT-3′ (SEQ ID NO: 1072)5′-AAAUUCCCUUAUUGUCCCUUCCAAA-3′ (SEQ ID NO: 1457)3′-AAUUUAAGGGAAUAACAGGGAAGGUUU-5′ (SEQ ID NO: 689) TTR-780 Target:5′-TTAAATTCCCTTATTGTCCCTTCCAAA-3′ (SEQ ID NO: 1073)5′-AAUUCCCUUAUUGUCCCUUCCAAAA-3′ (SEQ ID NO: 1458)3′-AUUUAAGGGAAUAACAGGGAAGGUUUU-5′ (SEQ ID NO: 690) TTR-781 Target:5′-TAAATTCCCTTATTGTCCCTTCCAAAA-3′ (SEQ ID NO: 1074)5′-UCCCUUAUUGUCCCUUCCAAAAAAA-3′ (SEQ ID NO: 1459)3′-UAAGGGAAUAACAGGGAAGGUUUUUUU-5′ (SEQ ID NO: 691) TTR-784 Target:5′-ATTCCCTTATTGTCCCTTCCAAAAAAA-3′ (SEQ ID NO: 1075)5′-AAAAAGAGAAUCAAAAUUUUACAAA-3′ (SEQ ID NO: 1460)3′-UUUUUUUCUCUUAGUUUUAAAAUGUUU-5′ (SEQ ID NO: 692) TTR-805 Target:5′-AAAAAAAGAGAATCAAAATTTTACAAA-3′ (SEQ ID NO: 1076)5′-AAAAGAGAAUCAAAAUUUUACAAAG-3′ (SEQ ID NO: 1461)3′-UUUUUUCUCUUAGUUUUAAAAUGUUUC-5′ (SEQ ID NO: 693) TTR-806 Target:5′-AAAAAAGAGAATCAAAATTTTACAAAG-3′ (SEQ ID NO: 1077)5′-AAAGAGAAUCAAAAUUUUACAAAGA-3′ (SEQ ID NO: 1462)3′-UUUUUCUCUUAGUUUUAAAAUGUUUCU-5′ (SEQ ID NO: 694) TTR-807 Target:5′-AAAAAGAGAATCAAAATTTTACAAAGA-3′ (SEQ ID NO: 1078)5′-AAGAGAAUCAAAAUUUUACAAAGAA-3′ (SEQ ID NO: 1463)3′-UUUUCUCUUAGUUUUAAAAUGUUUCUU-5′ (SEQ ID NO: 695) TTR-808 Target:5′-AAAAGAGAATCAAAATTTTACAAAGAA-3′ (SEQ ID NO: 1079)5′-AGAGAAUCAAAAUUUUACAAAGAAU-3′ (SEQ ID NO: 1464)3′-UUUCUCUUAGUUUUAAAAUGUUUCUUA-5′ (SEQ ID NO: 696) TTR-809 Target:5′-AAAGAGAATCAAAATTTTACAAAGAAT-3′ (SEQ ID NO: 1080)5′-GAGAAUCAAAAUUUUACAAAGAAUC-3′ (SEQ ID NO: 1465)3′-UUCUCUUAGUUUUAAAAUGUUUCUUAG-5′ (SEQ ID NO: 697) TTR-810 Target:5′-AAGAGAATCAAAATTTTACAAAGAATC-3′ (SEQ ID NO: 1081)5′-AGAAUCAAAAUUUUACAAAGAAUCA-3′ (SEQ ID NO: 1466)3′-UCUCUUAGUUUUAAAAUGUUUCUUAGU-5′ (SEQ ID NO: 698) TTR-811 Target:5′-AGAGAATCAAAATTTTACAAAGAATCA-3′ (SEQ ID NO: 1082)5′-GAAUCAAAAUUUUACAAAGAAUCAA-3′ (SEQ ID NO: 1467)3′-CUCUUAGUUUUAAAAUGUUUCUUAGUU-5′ (SEQ ID NO: 699) TTR-812 Target:5′-GAGAATCAAAATTTTACAAAGAATCAA-3′ (SEQ ID NO: 1083)5′-AAUCAAAAUUUUACAAAGAAUCAAA-3′ (SEQ ID NO: 1468)3′-UCUUAGUUUUAAAAUGUUUCUUAGUUU-5′ (SEQ ID NO: 700) TTR-813 Target:5′-AGAATCAAAATTTTACAAAGAATCAAA-3′ (SEQ ID NO: 1084)5′-AUCAAAAUUUUACAAAGAAUCAAAG-3′ (SEQ ID NO: 1469)3′-CUUAGUUUUAAAAUGUUUCUUAGUUUC-5′ (SEQ ID NO: 701) TTR-814 Target:5′-GAATCAAAATTTTACAAAGAATCAAAG-3′ (SEQ ID NO: 1085)5′-UCAAAAUUUUACAAAGAAUCAAAGG-3′ (SEQ ID NO: 1470)3′-UUAGUUUUAAAAUGUUUCUUAGUUUCC-5′ (SEQ ID NO: 702) TTR-815 Target:5′-AATCAAAATTTTACAAAGAATCAAAGG-3′ (SEQ ID NO: 1086)5′-CAAAAUUUUACAAAGAAUCAAAGGA-3′ (SEQ ID NO: 1471)3′-UAGUUUUAAAAUGUUUCUUAGUUUCCU-5′ (SEQ ID NO: 703) TTR-816 Target:5′-ATCAAAATTTTACAAAGAATCAAAGGA-3′ (SEQ ID NO: 1087)5′-AAAAUUUUACAAAGAAUCAAAGGAA-3′ (SEQ ID NO: 1472)3′-AGUUUUAAAAUGUUUCUUAGUUUCCUU-5′ (SEQ ID NO: 704) TTR-817 Target:5′-TCAAAATTTTACAAAGAATCAAAGGAA-3′ (SEQ ID NO: 1088)5′-AAAUUUUACAAAGAAUCAAAGGAAU-3′ (SEQ ID NO: 1473)3′-GUUUUAAAAUGUUUCUUAGUUUCCUUA-5′ (SEQ ID NO: 705) TTR-818 Target:5′-CAAAATTTTACAAAGAATCAAAGGAAT-3′ (SEQ ID NO: 1089)5′-AAUUUUACAAAGAAUCAAAGGAAUU-3′ (SEQ ID NO: 1474)3′-UUUUAAAAUGUUUCUUAGUUUCCUUAA-5′ (SEQ ID NO: 706) TTR-819 Target:5′-AAAATTTTACAAAGAATCAAAGGAATT-3′ (SEQ ID NO: 1090)5′-UUUUACAAAGAAUCAAAGGAAUUCU-3′ (SEQ ID NO: 1475)3′-UUAAAAUGUUUCUUAGUUUCCUUAAGA-5′ (SEQ ID NO: 707) TTR-821 Target:5′-AATTTTACAAAGAATCAAAGGAATTCT-3′ (SEQ ID NO: 1091)5′-UUUACAAAGAAUCAAAGGAAUUCUA-3′ (SEQ ID NO: 1476)3′-UAAAAUGUUUCUUAGUUUCCUUAAGAU-5′ (SEQ ID NO: 708) TTR-822 Target:5′-ATTTTACAAAGAATCAAAGGAATTCTA-3′ (SEQ ID NO: 1092)5′-UUACAAAGAAUCAAAGGAAUUCUAG-3′ (SEQ ID NO: 1477)3′-AAAAUGUUUCUUAGUUUCCUUAAGAUC-5′ (SEQ ID NO: 709) TTR-823 Target:5′-TTTTACAAAGAATCAAAGGAATTCTAG-3′ (SEQ ID NO: 1093)5′-UACAAAGAAUCAAAGGAAUUCUAGA-3′ (SEQ ID NO: 1478)3′-AAAUGUUUCUUAGUUUCCUUAAGAUCU-5′ (SEQ ID NO: 710) TTR-824 Target:5′-TTTACAAAGAATCAAAGGAATTCTAGA-3′ (SEQ ID NO: 1094)5′-ACAAAGAAUCAAAGGAAUUCUAGAA-3′ (SEQ ID NO: 1479)3′-AAUGUUUCUUAGUUUCCUUAAGAUCUU-5′ (SEQ ID NO: 711) TTR-825 Target:5′-TTACAAAGAATCAAAGGAATTCTAGAA-3′ (SEQ ID NO: 1095)5′-CAAAGAAUCAAAGGAAUUCUAGAAA-3′ (SEQ ID NO: 1480)3′-AUGUUUCUUAGUUUCCUUAAGAUCUUU-5′ (SEQ ID NO: 712) TTR-826 Target:5′-TACAAAGAATCAAAGGAATTCTAGAAA-3′ (SEQ ID NO: 1096)5′-AAAGAAUCAAAGGAAUUCUAGAAAG-3′ (SEQ ID NO: 1481)3′-UGUUUCUUAGUUUCCUUAAGAUCUUUC-5′ (SEQ ID NO: 713) TTR-827 Target:5′-ACAAAGAATCAAAGGAATTCTAGAAAG-3′ (SEQ ID NO: 1097)5′-AAGAAUCAAAGGAAUUCUAGAAAGU-3′ (SEQ ID NO: 1482)3′-GUUUCUUAGUUUCCUUAAGAUCUUUCA-5′ (SEQ ID NO: 714) TTR-828 Target:5′-CAAAGAATCAAAGGAATTCTAGAAAGT-3′ (SEQ ID NO: 1098)5′-AGAAUCAAAGGAAUUCUAGAAAGUA-3′ (SEQ ID NO: 1483)3′-UUUCUUAGUUUCCUUAAGAUCUUUCAU-5′ (SEQ ID NO: 715) TTR-829 Target:5′-AAAGAATCAAAGGAATTCTAGAAAGTA-3′ (SEQ ID NO: 1099)5′-GAAUCAAAGGAAUUCUAGAAAGUAU-3′ (SEQ ID NO: 1484)3′-UUCUUAGUUUCCUUAAGAUCUUUCAUA-5′ (SEQ ID NO: 716) TTR-830 Target:5′-AAGAATCAAAGGAATTCTAGAAAGTAT-3′ (SEQ ID NO: 1100)5′-AAUCAAAGGAAUUCUAGAAAGUAUC-3′ (SEQ ID NO: 1485)3′-UCUUAGUUUCCUUAAGAUCUUUCAUAG-5′ (SEQ ID NO: 717) TTR-831 Target:5′-AGAATCAAAGGAATTCTAGAAAGTATC-3′ (SEQ ID NO: 1101)5′-AUCAAAGGAAUUCUAGAAAGUAUCU-3′ (SEQ ID NO: 1486)3′-CUUAGUUUCCUUAAGAUCUUUCAUAGA-5′ (SEQ ID NO: 718) TTR-832 Target:5′-GAATCAAAGGAATTCTAGAAAGTATCT-3′ (SEQ ID NO: 1102)5′-UCAAAGGAAUUCUAGAAAGUAUCUG-3′ (SEQ ID NO: 1487)3′-UUAGUUUCCUUAAGAUCUUUCAUAGAC-5′ (SEQ ID NO: 719) TTR-833 Target:5′-AATCAAAGGAATTCTAGAAAGTATCTG-3′ (SEQ ID NO: 1103)5′-CAAAGGAAUUCUAGAAAGUAUCUGG-3′ (SEQ ID NO: 1488)3′-UAGUUUCCUUAAGAUCUUUCAUAGACC-5′ (SEQ ID NO: 720) TTR-834 Target:5′-ATCAAAGGAATTCTAGAAAGTATCTGG-3′ (SEQ ID NO: 1104)5′-AAAGGAAUUCUAGAAAGUAUCUGGG-3′ (SEQ ID NO: 1489)3′-AGUUUCCUUAAGAUCUUUCAUAGACCC-5′ (SEQ ID NO: 721) TTR-835 Target:5′-TCAAAGGAATTCTAGAAAGTATCTGGG-3′ (SEQ ID NO: 1105)5′-AGGAGAGAUCCAAAUUUCCAUUGUC-3′ (SEQ ID NO: 1490)3′-GAUCCUCUCUAGGUUUAAAGGUAACAG-5′ (SEQ ID NO: 722) TTR-869 Target:5′-CTAGGAGAGATCCAAATTTCCATTGTC-3′ (SEQ ID NO: 1106)5′-GGAGAGAUCCAAAUUUCCAUUGUCU-3′ (SEQ ID NO: 1491)3′-AUCCUCUCUAGGUUUAAAGGUAACAGA-5′ (SEQ ID NO: 723) TTR-870 Target:5′-TAGGAGAGATCCAAATTTCCATTGTCT-3′ (SEQ ID NO: 1107)5′-GAGAUCCAAAUUUCCAUUGUCUUGC-3′ (SEQ ID NO: 1492)3′-CUCUCUAGGUUUAAAGGUAACAGAACG-5′ (SEQ ID NO: 724) TTR-873 Target:5′-GAGAGATCCAAATTTCCATTGTCTTGC-3′ (SEQ ID NO: 1108)5′-AGAUCCAAAUUUCCAUUGUCUUGCA-3′ (SEQ ID NO: 1493)3′-UCUCUAGGUUUAAAGGUAACAGAACGU-5′ (SEQ ID NO: 725) TTR-874 Target:5′-AGAGATCCAAATTTCCATTGTCTTGCA-3′ (SEQ ID NO: 1109)5′-GAUCCAAAUUUCCAUUGUCUUGCAA-3′ (SEQ ID NO: 1494)3′-CUCUAGGUUUAAAGGUAACAGAACGUU-5′ (SEQ ID NO: 726) TTR-875 Target:5′-GAGATCCAAATTTCCATTGTCTTGCAA-3′ (SEQ ID NO: 1110)5′-AUCCAAAUUUCCAUUGUCUUGCAAG-3′ (SEQ ID NO: 1495)3′-UCUAGGUUUAAAGGUAACAGAACGUUC-5′ (SEQ ID NO: 727) TTR-876 Target:5′-AGATCCAAATTTCCATTGTCTTGCAAG-3′ (SEQ ID NO: 1111)5′-UCCAAAUUUCCAUUGUCUUGCAAGC-3′ (SEQ ID NO: 1496)3′-CUAGGUUUAAAGGUAACAGAACGUUCG-5′ (SEQ ID NO: 728) TTR-877 Target:5′-GATCCAAATTTCCATTGTCTTGCAAGC-3′ (SEQ ID NO: 1112)5′-CCAAAUUUCCAUUGUCUUGCAAGCA-3′ (SEQ ID NO: 1497)3′-UAGGUUUAAAGGUAACAGAACGUUCGU-5′ (SEQ ID NO: 729) TTR-878 Target:5′-ATCCAAATTTCCATTGTCTTGCAAGCA-3′ (SEQ ID NO: 1113)5′-CAAAUUUCCAUUGUCUUGCAAGCAA-3′ (SEQ ID NO: 1498)3′-AGGUUUAAAGGUAACAGAACGUUCGUU-5′ (SEQ ID NO: 730) TTR-879 Target:5′-TCCAAATTTCCATTGTCTTGCAAGCAA-3′ (SEQ ID NO: 1114)5′-AAAUUUCCAUUGUCUUGCAAGCAAA-3′ (SEQ ID NO: 1499)3′-GGUUUAAAGGUAACAGAACGUUCGUUU-5′ (SEQ ID NO: 731) TTR-880 Target:5′-CCAAATTTCCATTGTCTTGCAAGCAAA-3′ (SEQ ID NO: 1115)5′-AAUUUCCAUUGUCUUGCAAGCAAAG-3′ (SEQ ID NO: 1500)3′-GUUUAAAGGUAACAGAACGUUCGUUUC-5′ (SEQ ID NO: 732) TTR-881 Target:5′-CAAATTTCCATTGTCTTGCAAGCAAAG-3′ (SEQ ID NO: 1116)5′-AUUUCCAUUGUCUUGCAAGCAAAGC-3′ (SEQ ID NO: 1501)3′-UUUAAAGGUAACAGAACGUUCGUUUCG-5′ (SEQ ID NO: 733) TTR-882 Target:5′-AAATTTCCATTGTCTTGCAAGCAAAGC-3′ (SEQ ID NO: 1117)5′-UUUCCAUUGUCUUGCAAGCAAAGCA-3′ (SEQ ID NO: 1502)3′-UUAAAGGUAACAGAACGUUCGUUUCGU-5′ (SEQ ID NO: 734) TTR-883 Target:5′-AATTTCCATTGTCTTGCAAGCAAAGCA-3′ (SEQ ID NO: 1118)5′-UUCCAUUGUCUUGCAAGCAAAGCAC-3′ (SEQ ID NO: 1503)3′-UAAAGGUAACAGAACGUUCGUUUCGUG-5′ (SEQ ID NO: 735) TTR-884 Target:5′-ATTTCCATTGTCTTGCAAGCAAAGCAC-3′ (SEQ ID NO: 1119)5′-UCCAUUGUCUUGCAAGCAAAGCACG-3′ (SEQ ID NO: 1504)3′-AAAGGUAACAGAACGUUCGUUUCGUGC-5′ (SEQ ID NO: 736) TTR-885 Target:5′-TTTCCATTGTCTTGCAAGCAAAGCACG-3′ (SEQ ID NO: 1120)5′-CCAUUGUCUUGCAAGCAAAGCACGU-3′ (SEQ ID NO: 1505)3′-AAGGUAACAGAACGUUCGUUUCGUGCA-5′ (SEQ ID NO: 737) TTR-886 Target:5′-TTCCATTGTCTTGCAAGCAAAGCACGT-3′ (SEQ ID NO: 1121)5′-CAUUGUCUUGCAAGCAAAGCACGUA-3′ (SEQ ID NO: 1506)3′-AGGUAACAGAACGUUCGUUUCGUGCAU-5′ (SEQ ID NO: 738) TTR-887 Target:5′-TCCATTGTCTTGCAAGCAAAGCACGTA-3′ (SEQ ID NO: 1122)5′-AUUGUCUUGCAAGCAAAGCACGUAU-3′ (SEQ ID NO: 1507)3′-GGUAACAGAACGUUCGUUUCGUGCAUA-5′ (SEQ ID NO: 739) TTR-888 Target:5′-CCATTGTCTTGCAAGCAAAGCACGTAT-3′ (SEQ ID NO: 1123)5′-UUGUCUUGCAAGCAAAGCACGUAUU-3′ (SEQ ID NO: 1508)3′-GUAACAGAACGUUCGUUUCGUGCAUAA-5′ (SEQ ID NO: 740) TTR-889 Target:5′-CATTGTCTTGCAAGCAAAGCACGTATT-3′ (SEQ ID NO: 1124)5′-UGUCUUGCAAGCAAAGCACGUAUUA-3′ (SEQ ID NO: 1509)3′-UAACAGAACGUUCGUUUCGUGCAUAAU-5′ (SEQ ID NO: 741) TTR-890 Target:5′-ATTGTCTTGCAAGCAAAGCACGTATTA-3′ (SEQ ID NO: 1125)5′-GUCUUGCAAGCAAAGCACGUAUUAA-3′ (SEQ ID NO: 1510)3′-AACAGAACGUUCGUUUCGUGCAUAAUU-5′ (SEQ ID NO: 742) TTR-891 Target:5′-TTGTCTTGCAAGCAAAGCACGTATTAA-3′ (SEQ ID NO: 1126)5′-UCUUGCAAGCAAAGCACGUAUUAAA-3′ (SEQ ID NO: 1511)3′-ACAGAACGUUCGUUUCGUGCAUAAUUU-5′ (SEQ ID NO: 743) TTR-892 Target:5′-TGTCTTGCAAGCAAAGCACGTATTAAA-3′ (SEQ ID NO: 1127)5′-CUUGCAAGCAAAGCACGUAUUAAAU-3′ (SEQ ID NO: 1512)3′-CAGAACGUUCGUUUCGUGCAUAAUUUA-5′ (SEQ ID NO: 744) TTR-893 Target:5′-GTCTTGCAAGCAAAGCACGTATTAAAT-3′ (SEQ ID NO: 1128)5′-UUGCAAGCAAAGCACGUAUUAAAUA-3′ (SEQ ID NO: 1513)3′-AGAACGUUCGUUUCGUGCAUAAUUUAU-5′ (SEQ ID NO: 745) TTR-894 Target:5′-TCTTGCAAGCAAAGCACGTATTAAATA-3′ (SEQ ID NO: 1129)5′-UGCAAGCAAAGCACGUAUUAAAUAU-3′ (SEQ ID NO: 1514)3′-GAACGUUCGUUUCGUGCAUAAUUUAUA-5′ (SEQ ID NO: 746) TTR-895 Target:5′-CTTGCAAGCAAAGCACGTATTAAATAT-3′ (SEQ ID NO: 1130)5′-GCAAGCAAAGCACGUAUUAAAUAUG-3′ (SEQ ID NO: 1515)3′-AACGUUCGUUUCGUGCAUAAUUUAUAC-5′ (SEQ ID NO: 747) TTR-896 Target:5′-TTGCAAGCAAAGCACGTATTAAATATG-3′ (SEQ ID NO: 1131)5′-CAAGCAAAGCACGUAUUAAAUAUGA-3′ (SEQ ID NO: 1516)3′-ACGUUCGUUUCGUGCAUAAUUUAUACU-5′ (SEQ ID NO: 748) TTR-897 Target:5′-TGCAAGCAAAGCACGTATTAAATATGA-3′ (SEQ ID NO: 1132)5′-AAGCAAAGCACGUAUUAAAUAUGAU-3′ (SEQ ID NO: 1517)3′-CGUUCGUUUCGUGCAUAAUUUAUACUA-5′ (SEQ ID NO: 749) TTR-898 Target:5′-GCAAGCAAAGCACGTATTAAATATGAT-3′ (SEQ ID NO: 1133)5′-AGCAAAGCACGUAUUAAAUAUGAUC-3′ (SEQ ID NO: 1518)3′-GUUCGUUUCGUGCAUAAUUUAUACUAG-5′ (SEQ ID NO: 750) TTR-899 Target:5′-CAAGCAAAGCACGTATTAAATATGATC-3′ (SEQ ID NO: 1134)5′-GCAAAGCACGUAUUAAAUAUGAUCU-3′ (SEQ ID NO: 1519)3′-UUCGUUUCGUGCAUAAUUUAUACUAGA-5′ (SEQ ID NO: 751) TTR-900 Target:5′-AAGCAAAGCACGTATTAAATATGATCT-3′ (SEQ ID NO: 1135)5′-CAAAGCACGUAUUAAAUAUGAUCUG-3′ (SEQ ID NO: 1520)3′-UCGUUUCGUGCAUAAUUUAUACUAGAC-5′ (SEQ ID NO: 752) TTR-901 Target:5′-AGCAAAGCACGTATTAAATATGATCTG-3′ (SEQ ID NO: 1136)5′-AAAGCACGUAUUAAAUAUGAUCUGC-3′ (SEQ ID NO: 1521)3′-CGUUUCGUGCAUAAUUUAUACUAGACG-5′ (SEQ ID NO: 753) TTR-902 Target:5′-GCAAAGCACGTATTAAATATGATCTGC-3′ (SEQ ID NO: 1137)5′-AAGCACGUAUUAAAUAUGAUCUGCA-3′ (SEQ ID NO: 1522)3′-GUUUCGUGCAUAAUUUAUACUAGACGU-5′ (SEQ ID NO: 754) TTR-903 Target:5′-CAAAGCACGTATTAAATATGATCTGCA-3′ (SEQ ID NO: 1138)5′-AGCACGUAUUAAAUAUGAUCUGCAG-3′ (SEQ ID NO: 1523)3′-UUUCGUGCAUAAUUUAUACUAGACGUC-5′ (SEQ ID NO: 755) TTR-904 Target:5′-AAAGCACGTATTAAATATGATCTGCAG-3′ (SEQ ID NO: 1139)5′-GCACGUAUUAAAUAUGAUCUGCAGC-3′ (SEQ ID NO: 1524)3′-UUCGUGCAUAAUUUAUACUAGACGUCG-5′ (SEQ ID NO: 756) TTR-905 Target:5′-AAGCACGTATTAAATATGATCTGCAGC-3′ (SEQ ID NO: 1140)5′-CACGUAUUAAAUAUGAUCUGCAGCC-3′ (SEQ ID NO: 1525)3′-UCGUGCAUAAUUUAUACUAGACGUCGG-5′ (SEQ ID NO: 757) TTR-906 Target:5′-AGCACGTATTAAATATGATCTGCAGCC-3′ (SEQ ID NO: 1141)5′-CGUAUUAAAUAUGAUCUGCAGCCAU-3′ (SEQ ID NO: 1526)3′-GUGCAUAAUUUAUACUAGACGUCGGUA-5′ (SEQ ID NO: 758) TTR-908 Target:5′-CACGTATTAAATATGATCTGCAGCCAT-3′ (SEQ ID NO: 1142)5′-GUAUUAAAUAUGAUCUGCAGCCAUU-3′ (SEQ ID NO: 1527)3′-UGCAUAAUUUAUACUAGACGUCGGUAA-5′ (SEQ ID NO: 759) TTR-909 Target:5′-ACGTATTAAATATGATCTGCAGCCATT-3′ (SEQ ID NO: 1143)5′-AUUAAAUAUGAUCUGCAGCCAUUAA-3′ (SEQ ID NO: 1528)3′-CAUAAUUUAUACUAGACGUCGGUAAUU-5′ (SEQ ID NO: 760) TTR-911 Target:5′-GTATTAAATATGATCTGCAGCCATTAA-3′ (SEQ ID NO: 1144)5′-UUAAAUAUGAUCUGCAGCCAUUAAA-3′ (SEQ ID NO: 1529)3′-AUAAUUUAUACUAGACGUCGGUAAUUU-5′ (SEQ ID NO: 761) TTR-912 Target:5′-TATTAAATATGATCTGCAGCCATTAAA-3′ (SEQ ID NO: 1145)5′-UAAAUAUGAUCUGCAGCCAUUAAAA-3′ (SEQ ID NO: 1530)3′-UAAUUUAUACUAGACGUCGGUAAUUUU-5′ (SEQ ID NO: 762) TTR-913 Target:5′-ATTAAATATGATCTGCAGCCATTAAAA-3′ (SEQ ID NO: 1146)5′-AAAUAUGAUCUGCAGCCAUUAAAAA-3′ (SEQ ID NO: 1531)3′-AAUUUAUACUAGACGUCGGUAAUUUUU-5′ (SEQ ID NO: 763) TTR-914 Target:5′-TTAAATATGATCTGCAGCCATTAAAAA-3′ (SEQ ID NO: 1147)5′-AAUAUGAUCUGCAGCCAUUAAAAAG-3′ (SEQ ID NO: 1532)3′-AUUUAUACUAGACGUCGGUAAUUUUUC-5′ (SEQ ID NO: 764) TTR-915 Target:5′-TAAATATGATCTGCAGCCATTAAAAAG-3′ (SEQ ID NO: 1148)5′-AUAUGAUCUGCAGCCAUUAAAAAGA-3′ (SEQ ID NO: 1533)3′-UUUAUACUAGACGUCGGUAAUUUUUCU-5′ (SEQ ID NO: 765) TTR-916 Target:5′-AAATATGATCTGCAGCCATTAAAAAGA-3′ (SEQ ID NO: 1149)5′-UAUGAUCUGCAGCCAUUAAAAAGAC-3′ (SEQ ID NO: 1534)3′-UUAUACUAGACGUCGGUAAUUUUUCUG-5′ (SEQ ID NO: 766) TTR-917 Target:5′-AATATGATCTGCAGCCATTAAAAAGAC-3′ (SEQ ID NO: 1150)5′-AUGAUCUGCAGCCAUUAAAAAGACA-3′ (SEQ ID NO: 1535)3′-UAUACUAGACGUCGGUAAUUUUUCUGU-5′ (SEQ ID NO: 767) TTR-918 Target:5′-ATATGATCTGCAGCCATTAAAAAGACA-3′ (SEQ ID NO: 1151)5′-UGAUCUGCAGCCAUUAAAAAGACAC-3′ (SEQ ID NO: 1536)3′-AUACUAGACGUCGGUAAUUUUUCUGUG-5′ (SEQ ID NO: 768) TTR-919 Target:5′-TATGATCTGCAGCCATTAAAAAGACAC-3′ (SEQ ID NO: 1152)

TABLE 4 DsiRNA Target Sequences (21mers) in Transthyretin mRNATTR-27 21 nt Target: 5′-GUUGACUAAGUCAAUAAUCAG-3′ (SEQ ID NO: 1537)TTR-28 21 nt Target: 5′-UUGACUAAGUCAAUAAUCAGA-3′ (SEQ ID NO: 1538)TTR-29 21 nt Target: 5′-UGACUAAGUCAAUAAUCAGAA-3′ (SEQ ID NO: 1539)TTR-30 21 nt Target: 5′-GACUAAGUCAAUAAUCAGAAU-3′ (SEQ ID NO: 1540)TTR-31 21 nt Target: 5′-ACUAAGUCAAUAAUCAGAAUC-3′ (SEQ ID NO: 1541)TTR-32 21 nt Target: 5′-CUAAGUCAAUAAUCAGAAUCA-3′ (SEQ ID NO: 1542)TTR-33 21 nt Target: 5′-UAAGUCAAUAAUCAGAAUCAG-3′ (SEQ ID NO: 1543)TTR-34 21 nt Target: 5′-AAGUCAAUAAUCAGAAUCAGC-3′ (SEQ ID NO: 1544)TTR-35 21 nt Target: 5′-AGUCAAUAAUCAGAAUCAGCA-3′ (SEQ ID NO: 1545)TTR-36 21 nt Target: 5′-GUCAAUAAUCAGAAUCAGCAG-3′ (SEQ ID NO: 1546)TTR-37 21 nt Target: 5′-UCAAUAAUCAGAAUCAGCAGG-3′ (SEQ ID NO: 1547)TTR-38 21 nt Target: 5′-CAAUAAUCAGAAUCAGCAGGU-3′ (SEQ ID NO: 1548)TTR-39 21 nt Target: 5′-AAUAAUCAGAAUCAGCAGGUU-3′ (SEQ ID NO: 1549)TTR-40 21 nt Target: 5′-AUAAUCAGAAUCAGCAGGUUU-3′ (SEQ ID NO: 1550)TTR-41 21 nt Target: 5′-UAAUCAGAAUCAGCAGGUUUG-3′ (SEQ ID NO: 1551)TTR-43 21 nt Target: 5′-AUCAGAAUCAGCAGGUUUGCA-3′ (SEQ ID NO: 1552)TTR-44 21 nt Target: 5′-UCAGAAUCAGCAGGUUUGCAG-3′ (SEQ ID NO: 1553)TTR-46 21 nt Target: 5′-AGAAUCAGCAGGUUUGCAGUC-3′ (SEQ ID NO: 1554)TTR-47 21 nt Target: 5′-GAAUCAGCAGGUUUGCAGUCA-3′ (SEQ ID NO: 1555)TTR-59 21 nt Target: 5′-UUGCAGUCAGAUUGGCAGGGA-3′ (SEQ ID NO: 1556)TTR-84 21 nt Target: 5′-CAGCCUAGCUCAGGAGAAGUG-3′ (SEQ ID NO: 1557)TTR-87 21 nt Target: 5′-CCUAGCUCAGGAGAAGUGAGU-3′ (SEQ ID NO: 1558)TTR-88 21 nt Target: 5′-CUAGCUCAGGAGAAGUGAGUA-3′ (SEQ ID NO: 1559)TTR-89 21 nt Target: 5′-UAGCUCAGGAGAAGUGAGUAU-3′ (SEQ ID NO: 1560)TTR-90 21 nt Target: 5′-AGCUCAGGAGAAGUGAGUAUA-3′ (SEQ ID NO: 1561)TTR-92 21 nt Target: 5′-CUCAGGAGAAGUGAGUAUAAA-3′ (SEQ ID NO: 1562)TTR-126 21 nt Target: 5′-GAGCAGCCAUCACAGAAGUCC-3′ (SEQ ID NO: 1563)TTR-127 21 nt Target: 5′-AGCAGCCAUCACAGAAGUCCA-3′ (SEQ ID NO: 1564)TTR-128 21 nt Target: 5′-GCAGCCAUCACAGAAGUCCAC-3′ (SEQ ID NO: 1565)TTR-129 21 nt Target: 5′-CAGCCAUCACAGAAGUCCACU-3′ (SEQ ID NO: 1566)TTR-130 21 nt Target: 5′-AGCCAUCACAGAAGUCCACUC-3′ (SEQ ID NO: 1567)TTR-131 21 nt Target: 5′-GCCAUCACAGAAGUCCACUCA-3′ (SEQ ID NO: 1568)TTR-132 21 nt Target: 5′-CCAUCACAGAAGUCCACUCAU-3′ (SEQ ID NO: 1569)TTR-134 21 nt Target: 5′-AUCACAGAAGUCCACUCAUUC-3′ (SEQ ID NO: 1570)TTR-135 21 nt Target: 5′-UCACAGAAGUCCACUCAUUCU-3′ (SEQ ID NO: 1571)TTR-150 21 nt Target: 5′-CAUUCUUGGCAGGAUGGCUUC-3′ (SEQ ID NO: 1572)TTR-151 21 nt Target: 5′-AUUCUUGGCAGGAUGGCUUCU-3′ (SEQ ID NO: 1573)TTR-152 21 nt Target: 5′-UUCUUGGCAGGAUGGCUUCUC-3′ (SEQ ID NO: 1574)TTR-153 21 nt Target: 5′-UCUUGGCAGGAUGGCUUCUCA-3′ (SEQ ID NO: 1575)TTR-154 21 nt Target: 5′-CUUGGCAGGAUGGCUUCUCAU-3′ (SEQ ID NO: 1576)TTR-155 21 nt Target: 5′-UUGGCAGGAUGGCUUCUCAUC-3′ (SEQ ID NO: 1577)TTR-156 21 nt Target: 5′-UGGCAGGAUGGCUUCUCAUCG-3′ (SEQ ID NO: 1578)TTR-157 21 nt Target: 5′-GGCAGGAUGGCUUCUCAUCGU-3′ (SEQ ID NO: 1579)TTR-158 21 nt Target: 5′-GCAGGAUGGCUUCUCAUCGUC-3′ (SEQ ID NO: 1580)TTR-159 21 nt Target: 5′-CAGGAUGGCUUCUCAUCGUCU-3′ (SEQ ID NO: 1581)TTR-160 21 nt Target: 5′-AGGAUGGCUUCUCAUCGUCUG-3′ (SEQ ID NO: 1582)TTR-161 21 nt Target: 5′-GGAUGGCUUCUCAUCGUCUGC-3′ (SEQ ID NO: 1583)TTR-162 21 nt Target: 5′-GAUGGCUUCUCAUCGUCUGCU-3′ (SEQ ID NO: 1584)TTR-163 21 nt Target: 5′-AUGGCUUCUCAUCGUCUGCUC-3′ (SEQ ID NO: 1585)TTR-164 21 nt Target: 5′-UGGCUUCUCAUCGUCUGCUCC-3′ (SEQ ID NO: 1586)TTR-165 21 nt Target: 5′-GGCUUCUCAUCGUCUGCUCCU-3′ (SEQ ID NO: 1587)TTR-186 21 nt Target: 5′-CCUCUGCCUUGCUGGACUGGU-3′ (SEQ ID NO: 1588)TTR-187 21 nt Target: 5′-CUCUGCCUUGCUGGACUGGUA-3′ (SEQ ID NO: 1589)TTR-234 21 nt Target: 5′-CACCGGUGAAUCCAAGUGUCC-3′ (SEQ ID NO: 1590)TTR-238 21 nt Target: 5′-GGUGAAUCCAAGUGUCCUCUG-3′ (SEQ ID NO: 1591)TTR-239 21 nt Target: 5′-GUGAAUCCAAGUGUCCUCUGA-3′ (SEQ ID NO: 1592)TTR-240 21 nt Target: 5′-UGAAUCCAAGUGUCCUCUGAU-3′ (SEQ ID NO: 1593)TTR-241 21 nt Target: 5′-GAAUCCAAGUGUCCUCUGAUG-3′ (SEQ ID NO: 1594)TTR-242 21 nt Target: 5′-AAUCCAAGUGUCCUCUGAUGG-3′ (SEQ ID NO: 1595)TTR-243 21 nt Target: 5′-AUCCAAGUGUCCUCUGAUGGU-3′ (SEQ ID NO: 1596)TTR-244 21 nt Target: 5′-UCCAAGUGUCCUCUGAUGGUC-3′ (SEQ ID NO: 1597)TTR-245 21 nt Target: 5′-CCAAGUGUCCUCUGAUGGUCA-3′ (SEQ ID NO: 1598)TTR-246 21 nt Target: 5′-CAAGUGUCCUCUGAUGGUCAA-3′ (SEQ ID NO: 1599)TTR-247 21 nt Target: 5′-AAGUGUCCUCUGAUGGUCAAA-3′ (SEQ ID NO: 1600)TTR-248 21 nt Target: 5′-AGUGUCCUCUGAUGGUCAAAG-3′ (SEQ ID NO: 1601)TTR-249 21 nt Target: 5′-GUGUCCUCUGAUGGUCAAAGU-3′ (SEQ ID NO: 1602)TTR-250 21 nt Target: 5′-UGUCCUCUGAUGGUCAAAGUU-3′ (SEQ ID NO: 1603)TTR-251 21 nt Target: 5′-GUCCUCUGAUGGUCAAAGUUC-3′ (SEQ ID NO: 1604)TTR-252 21 nt Target: 5′-UCCUCUGAUGGUCAAAGUUCU-3′ (SEQ ID NO: 1605)TTR-253 21 nt Target: 5′-CCUCUGAUGGUCAAAGUUCUA-3′ (SEQ ID NO: 1606)TTR-254 21 nt Target: 5′-CUCUGAUGGUCAAAGUUCUAG-3′ (SEQ ID NO: 1607)TTR-255 21 nt Target: 5′-UCUGAUGGUCAAAGUUCUAGA-3′ (SEQ ID NO: 1608)TTR-256 21 nt Target: 5′-CUGAUGGUCAAAGUUCUAGAU-3′ (SEQ ID NO: 1609)TTR-257 21 nt Target: 5′-UGAUGGUCAAAGUUCUAGAUG-3′ (SEQ ID NO: 1610)TTR-258 21 nt Target: 5′-GAUGGUCAAAGUUCUAGAUGC-3′ (SEQ ID NO: 1611)TTR-346 21 nt Target: 5′-GAGCCAUUUGCCUCUGGGAAA-3′ (SEQ ID NO: 1612)TTR-347 21 nt Target: 5′-AGCCAUUUGCCUCUGGGAAAA-3′ (SEQ ID NO: 1613)TTR-348 21 nt Target: 5′-GCCAUUUGCCUCUGGGAAAAC-3′ (SEQ ID NO: 1614)TTR-349 21 nt Target: 5′-CCAUUUGCCUCUGGGAAAACC-3′ (SEQ ID NO: 1615)TTR-350 21 nt Target: 5′-CAUUUGCCUCUGGGAAAACCA-3′ (SEQ ID NO: 1616)TTR-351 21 nt Target: 5′-AUUUGCCUCUGGGAAAACCAG-3′ (SEQ ID NO: 1617)TTR-352 21 nt Target: 5′-UUUGCCUCUGGGAAAACCAGU-3′ (SEQ ID NO: 1618)TTR-353 21 nt Target: 5′-UUGCCUCUGGGAAAACCAGUG-3′ (SEQ ID NO: 1619)TTR-354 21 nt Target: 5′-UGCCUCUGGGAAAACCAGUGA-3′ (SEQ ID NO: 1620)TTR-355 21 nt Target: 5′-GCCUCUGGGAAAACCAGUGAG-3′ (SEQ ID NO: 1621)TTR-356 21 nt Target: 5′-CCUCUGGGAAAACCAGUGAGU-3′ (SEQ ID NO: 1622)TTR-357 21 nt Target: 5′-CUCUGGGAAAACCAGUGAGUC-3′ (SEQ ID NO: 1623)TTR-358 21 nt Target: 5′-UCUGGGAAAACCAGUGAGUCU-3′ (SEQ ID NO: 1624)TTR-359 21 nt Target: 5′-CUGGGAAAACCAGUGAGUCUG-3′ (SEQ ID NO: 1625)TTR-360 21 nt Target: 5′-UGGGAAAACCAGUGAGUCUGG-3′ (SEQ ID NO: 1626)TTR-361 21 nt Target: 5′-GGGAAAACCAGUGAGUCUGGA-3′ (SEQ ID NO: 1627)TTR-381 21 nt Target: 5′-AGAGCUGCAUGGGCUCACAAC-3′ (SEQ ID NO: 1628)TTR-382 21 nt Target: 5′-GAGCUGCAUGGGCUCACAACU-3′ (SEQ ID NO: 1629)TTR-383 21 nt Target: 5′-AGCUGCAUGGGCUCACAACUG-3′ (SEQ ID NO: 1630)TTR-384 21 nt Target: 5′-GCUGCAUGGGCUCACAACUGA-3′ (SEQ ID NO: 1631)TTR-385 21 nt Target: 5′-CUGCAUGGGCUCACAACUGAG-3′ (SEQ ID NO: 1632)TTR-386 21 nt Target: 5′-UGCAUGGGCUCACAACUGAGG-3′ (SEQ ID NO: 1633)TTR-387 21 nt Target: 5′-GCAUGGGCUCACAACUGAGGA-3′ (SEQ ID NO: 1634)TTR-388 21 nt Target: 5′-CAUGGGCUCACAACUGAGGAG-3′ (SEQ ID NO: 1635)TTR-389 21 nt Target: 5′-AUGGGCUCACAACUGAGGAGG-3′ (SEQ ID NO: 1636)TTR-390 21 nt Target: 5′-UGGGCUCACAACUGAGGAGGA-3′ (SEQ ID NO: 1637)TTR-391 21 nt Target: 5′-GGGCUCACAACUGAGGAGGAA-3′ (SEQ ID NO: 1638)TTR-392 21 nt Target: 5′-GGCUCACAACUGAGGAGGAAU-3′ (SEQ ID NO: 1639)TTR-393 21 nt Target: 5′-GCUCACAACUGAGGAGGAAUU-3′ (SEQ ID NO: 1640)TTR-394 21 nt Target: 5′-CUCACAACUGAGGAGGAAUUU-3′ (SEQ ID NO: 1641)TTR-395 21 nt Target: 5′-UCACAACUGAGGAGGAAUUUG-3′ (SEQ ID NO: 1642)TTR-396 21 nt Target: 5′-CACAACUGAGGAGGAAUUUGU-3′ (SEQ ID NO: 1643)TTR-398 21 nt Target: 5′-CAACUGAGGAGGAAUUUGUAG-3′ (SEQ ID NO: 1644)TTR-399 21 nt Target: 5′-AACUGAGGAGGAAUUUGUAGA-3′ (SEQ ID NO: 1645)TTR-400 21 nt Target: 5′-ACUGAGGAGGAAUUUGUAGAA-3′ (SEQ ID NO: 1646)TTR-401 21 nt Target: 5′-CUGAGGAGGAAUUUGUAGAAG-3′ (SEQ ID NO: 1647)TTR-402 21 nt Target: 5′-UGAGGAGGAAUUUGUAGAAGG-3′ (SEQ ID NO: 1648)TTR-403 21 nt Target: 5′-GAGGAGGAAUUUGUAGAAGGG-3′ (SEQ ID NO: 1649)TTR-404 21 nt Target: 5′-AGGAGGAAUUUGUAGAAGGGA-3′ (SEQ ID NO: 1650)TTR-405 21 nt Target: 5′-GGAGGAAUUUGUAGAAGGGAU-3′ (SEQ ID NO: 1651)TTR-406 21 nt Target: 5′-GAGGAAUUUGUAGAAGGGAUA-3′ (SEQ ID NO: 1652)TTR-407 21 nt Target: 5′-AGGAAUUUGUAGAAGGGAUAU-3′ (SEQ ID NO: 1653)TTR-408 21 nt Target: 5′-GGAAUUUGUAGAAGGGAUAUA-3′ (SEQ ID NO: 1654)TTR-409 21 nt Target: 5′-GAAUUUGUAGAAGGGAUAUAC-3′ (SEQ ID NO: 1655)TTR-410 21 nt Target: 5′-AAUUUGUAGAAGGGAUAUACA-3′ (SEQ ID NO: 1656)TTR-411 21 nt Target: 5′-AUUUGUAGAAGGGAUAUACAA-3′ (SEQ ID NO: 1657)TTR-412 21 nt Target: 5′-UUUGUAGAAGGGAUAUACAAA-3′ (SEQ ID NO: 1658)TTR-413 21 nt Target: 5′-UUGUAGAAGGGAUAUACAAAG-3′ (SEQ ID NO: 1659)TTR-414 21 nt Target: 5′-UGUAGAAGGGAUAUACAAAGU-3′ (SEQ ID NO: 1660)TTR-415 21 nt Target: 5′-GUAGAAGGGAUAUACAAAGUG-3′ (SEQ ID NO: 1661)TTR-416 21 nt Target: 5′-UAGAAGGGAUAUACAAAGUGG-3′ (SEQ ID NO: 1662)TTR-417 21 nt Target: 5′-AGAAGGGAUAUACAAAGUGGA-3′ (SEQ ID NO: 1663)TTR-418 21 nt Target: 5′-GAAGGGAUAUACAAAGUGGAA-3′ (SEQ ID NO: 1664)TTR-419 21 nt Target: 5′-AAGGGAUAUACAAAGUGGAAA-3′ (SEQ ID NO: 1665)TTR-420 21 nt Target: 5′-AGGGAUAUACAAAGUGGAAAU-3′ (SEQ ID NO: 1666)TTR-421 21 nt Target: 5′-GGGAUAUACAAAGUGGAAAUA-3′ (SEQ ID NO: 1667)TTR-422 21 nt Target: 5′-GGAUAUACAAAGUGGAAAUAG-3′ (SEQ ID NO: 1668)TTR-423 21 nt Target: 5′-GAUAUACAAAGUGGAAAUAGA-3′ (SEQ ID NO: 1669)TTR-424 21 nt Target: 5′-AUAUACAAAGUGGAAAUAGAC-3′ (SEQ ID NO: 1670)TTR-425 21 nt Target: 5′-UAUACAAAGUGGAAAUAGACA-3′ (SEQ ID NO: 1671)TTR-426 21 nt Target: 5′-AUACAAAGUGGAAAUAGACAC-3′ (SEQ ID NO: 1672)TTR-427 21 nt Target: 5′-UACAAAGUGGAAAUAGACACC-3′ (SEQ ID NO: 1673)TTR-428 21 nt Target: 5′-ACAAAGUGGAAAUAGACACCA-3′ (SEQ ID NO: 1674)TTR-429 21 nt Target: 5′-CAAAGUGGAAAUAGACACCAA-3′ (SEQ ID NO: 1675)TTR-430 21 nt Target: 5′-AAAGUGGAAAUAGACACCAAA-3′ (SEQ ID NO: 1676)TTR-431 21 nt Target: 5′-AAGUGGAAAUAGACACCAAAU-3′ (SEQ ID NO: 1677)TTR-432 21 nt Target: 5′-AGUGGAAAUAGACACCAAAUC-3′ (SEQ ID NO: 1678)TTR-433 21 nt Target: 5′-GUGGAAAUAGACACCAAAUCU-3′ (SEQ ID NO: 1679)TTR-434 21 nt Target: 5′-UGGAAAUAGACACCAAAUCUU-3′ (SEQ ID NO: 1680)TTR-435 21 nt Target: 5′-GGAAAUAGACACCAAAUCUUA-3′ (SEQ ID NO: 1681)TTR-436 21 nt Target: 5′-GAAAUAGACACCAAAUCUUAC-3′ (SEQ ID NO: 1682)TTR-437 21 nt Target: 5′-AAAUAGACACCAAAUCUUACU-3′ (SEQ ID NO: 1683)TTR-439 21 nt Target: 5′-AUAGACACCAAAUCUUACUGG-3′ (SEQ ID NO: 1684)TTR-440 21 nt Target: 5′-UAGACACCAAAUCUUACUGGA-3′ (SEQ ID NO: 1685)TTR-462 21 nt Target: 5′-GGCACUUGGCAUCUCCCCAUU-3′ (SEQ ID NO: 1686)TTR-463 21 nt Target: 5′-GCACUUGGCAUCUCCCCAUUC-3′ (SEQ ID NO: 1687)TTR-464 21 nt Target: 5′-CACUUGGCAUCUCCCCAUUCC-3′ (SEQ ID NO: 1688)TTR-465 21 nt Target: 5′-ACUUGGCAUCUCCCCAUUCCA-3′ (SEQ ID NO: 1689)TTR-466 21 nt Target: 5′-CUUGGCAUCUCCCCAUUCCAU-3′ (SEQ ID NO: 1690)TTR-467 21 nt Target: 5′-UUGGCAUCUCCCCAUUCCAUG-3′ (SEQ ID NO: 1691)TTR-468 21 nt Target: 5′-UGGCAUCUCCCCAUUCCAUGA-3′ (SEQ ID NO: 1692)TTR-469 21 nt Target: 5′-GGCAUCUCCCCAUUCCAUGAG-3′ (SEQ ID NO: 1693)TTR-470 21 nt Target: 5′-GCAUCUCCCCAUUCCAUGAGC-3′ (SEQ ID NO: 1694)TTR-471 21 nt Target: 5′-CAUCUCCCCAUUCCAUGAGCA-3′ (SEQ ID NO: 1695)TTR-472 21 nt Target: 5′-AUCUCCCCAUUCCAUGAGCAU-3′ (SEQ ID NO: 1696)TTR-473 21 nt Target: 5′-UCUCCCCAUUCCAUGAGCAUG-3′ (SEQ ID NO: 1697)TTR-474 21 nt Target: 5′-CUCCCCAUUCCAUGAGCAUGC-3′ (SEQ ID NO: 1698)TTR-482 21 nt Target: 5′-UCCAUGAGCAUGCAGAGGUGG-3′ (SEQ ID NO: 1699)TTR-483 21 nt Target: 5′-CCAUGAGCAUGCAGAGGUGGU-3′ (SEQ ID NO: 1700)TTR-484 21 nt Target: 5′-CAUGAGCAUGCAGAGGUGGUA-3′ (SEQ ID NO: 1701)TTR-485 21 nt Target: 5′-AUGAGCAUGCAGAGGUGGUAU-3′ (SEQ ID NO: 1702)TTR-489 21 nt Target: 5′-GCAUGCAGAGGUGGUAUUCAC-3′ (SEQ ID NO: 1703)TTR-493 21 nt Target: 5′-GCAGAGGUGGUAUUCACAGCC-3′ (SEQ ID NO: 1704)TTR-494 21 nt Target: 5′-CAGAGGUGGUAUUCACAGCCA-3′ (SEQ ID NO: 1705)TTR-581 21 nt Target: 5′-CUGUCGUCACCAAUCCCAAGG-3′ (SEQ ID NO: 1706)TTR-631 21 nt Target: 5′-AAGGACGAGGGAUGGGAUUUC-3′ (SEQ ID NO: 1707)TTR-632 21 nt Target: 5′-AGGACGAGGGAUGGGAUUUCA-3′ (SEQ ID NO: 1708)TTR-635 21 nt Target: 5′-ACGAGGGAUGGGAUUUCAUGU-3′ (SEQ ID NO: 1709)TTR-636 21 nt Target: 5′-CGAGGGAUGGGAUUUCAUGUA-3′ (SEQ ID NO: 1710)TTR-637 21 nt Target: 5′-GAGGGAUGGGAUUUCAUGUAA-3′ (SEQ ID NO: 1711)TTR-639 21 nt Target: 5′-GGGAUGGGAUUUCAUGUAACC-3′ (SEQ ID NO: 1712)TTR-640 21 nt Target: 5′-GGAUGGGAUUUCAUGUAACCA-3′ (SEQ ID NO: 1713)TTR-641 21 nt Target: 5′-GAUGGGAUUUCAUGUAACCAA-3′ (SEQ ID NO: 1714)TTR-642 21 nt Target: 5′-AUGGGAUUUCAUGUAACCAAG-3′ (SEQ ID NO: 1715)TTR-643 21 nt Target: 5′-UGGGAUUUCAUGUAACCAAGA-3′ (SEQ ID NO: 1716)TTR-644 21 nt Target: 5′-GGGAUUUCAUGUAACCAAGAG-3′ (SEQ ID NO: 1717)TTR-645 21 nt Target: 5′-GGAUUUCAUGUAACCAAGAGU-3′ (SEQ ID NO: 1718)TTR-646 21 nt Target: 5′-GAUUUCAUGUAACCAAGAGUA-3′ (SEQ ID NO: 1719)TTR-647 21 nt Target: 5′-AUUUCAUGUAACCAAGAGUAU-3′ (SEQ ID NO: 1720)TTR-648 21 nt Target: 5′-UUUCAUGUAACCAAGAGUAUU-3′ (SEQ ID NO: 1721)TTR-649 21 nt Target: 5′-UUCAUGUAACCAAGAGUAUUC-3′ (SEQ ID NO: 1722)TTR-650 21 nt Target: 5′-UCAUGUAACCAAGAGUAUUCC-3′ (SEQ ID NO: 1723)TTR-651 21 nt Target: 5′-CAUGUAACCAAGAGUAUUCCA-3′ (SEQ ID NO: 1724)TTR-652 21 nt Target: 5′-AUGUAACCAAGAGUAUUCCAU-3′ (SEQ ID NO: 1725)TTR-653 21 nt Target: 5′-UGUAACCAAGAGUAUUCCAUU-3′ (SEQ ID NO: 1726)TTR-654 21 nt Target: 5′-GUAACCAAGAGUAUUCCAUUU-3′ (SEQ ID NO: 1727)TTR-655 21 nt Target: 5′-UAACCAAGAGUAUUCCAUUUU-3′ (SEQ ID NO: 1728)TTR-656 21 nt Target: 5′-AACCAAGAGUAUUCCAUUUUU-3′ (SEQ ID NO: 1729)TTR-657 21 nt Target: 5′-ACCAAGAGUAUUCCAUUUUUA-3′ (SEQ ID NO: 1730)TTR-658 21 nt Target: 5′-CCAAGAGUAUUCCAUUUUUAC-3′ (SEQ ID NO: 1731)TTR-659 21 nt Target: 5′-CAAGAGUAUUCCAUUUUUACU-3′ (SEQ ID NO: 1732)TTR-660 21 nt Target: 5′-AAGAGUAUUCCAUUUUUACUA-3′ (SEQ ID NO: 1733)TTR-661 21 nt Target: 5′-AGAGUAUUCCAUUUUUACUAA-3′ (SEQ ID NO: 1734)TTR-662 21 nt Target: 5′-GAGUAUUCCAUUUUUACUAAA-3′ (SEQ ID NO: 1735)TTR-663 21 nt Target: 5′-AGUAUUCCAUUUUUACUAAAG-3′ (SEQ ID NO: 1736)TTR-664 21 nt Target: 5′-GUAUUCCAUUUUUACUAAAGC-3′ (SEQ ID NO: 1737)TTR-665 21 nt Target: 5′-UAUUCCAUUUUUACUAAAGCA-3′ (SEQ ID NO: 1738)TTR-666 21 nt Target: 5′-AUUCCAUUUUUACUAAAGCAG-3′ (SEQ ID NO: 1739)TTR-667 21 nt Target: 5′-UUCCAUUUUUACUAAAGCAGU-3′ (SEQ ID NO: 1740)TTR-668 21 nt Target: 5′-UCCAUUUUUACUAAAGCAGUG-3′ (SEQ ID NO: 1741)TTR-669 21 nt Target: 5′-CCAUUUUUACUAAAGCAGUGU-3′ (SEQ ID NO: 1742)TTR-670 21 nt Target: 5′-CAUUUUUACUAAAGCAGUGUU-3′ (SEQ ID NO: 1743)TTR-671 21 nt Target: 5′-AUUUUUACUAAAGCAGUGUUU-3′ (SEQ ID NO: 1744)TTR-672 21 nt Target: 5′-UUUUUACUAAAGCAGUGUUUU-3′ (SEQ ID NO: 1745)TTR-673 21 nt Target: 5′-UUUUACUAAAGCAGUGUUUUC-3′ (SEQ ID NO: 1746)TTR-674 21 nt Target: 5′-UUUACUAAAGCAGUGUUUUCA-3′ (SEQ ID NO: 1747)TTR-675 21 nt Target: 5′-UUACUAAAGCAGUGUUUUCAC-3′ (SEQ ID NO: 1748)TTR-676 21 nt Target: 5′-UACUAAAGCAGUGUUUUCACC-3′ (SEQ ID NO: 1749)TTR-677 21 nt Target: 5′-ACUAAAGCAGUGUUUUCACCU-3′ (SEQ ID NO: 1750)TTR-678 21 nt Target: 5′-CUAAAGCAGUGUUUUCACCUC-3′ (SEQ ID NO: 1751)TTR-679 21 nt Target: 5′-UAAAGCAGUGUUUUCACCUCA-3′ (SEQ ID NO: 1752)TTR-680 21 nt Target: 5′-AAAGCAGUGUUUUCACCUCAU-3′ (SEQ ID NO: 1753)TTR-681 21 nt Target: 5′-AAGCAGUGUUUUCACCUCAUA-3′ (SEQ ID NO: 1754)TTR-682 21 nt Target: 5′-AGCAGUGUUUUCACCUCAUAU-3′ (SEQ ID NO: 1755)TTR-683 21 nt Target: 5′-GCAGUGUUUUCACCUCAUAUG-3′ (SEQ ID NO: 1756)TTR-684 21 nt Target: 5′-CAGUGUUUUCACCUCAUAUGC-3′ (SEQ ID NO: 1757)TTR-685 21 nt Target: 5′-AGUGUUUUCACCUCAUAUGCU-3′ (SEQ ID NO: 1758)TTR-686 21 nt Target: 5′-GUGUUUUCACCUCAUAUGCUA-3′ (SEQ ID NO: 1759)TTR-687 21 nt Target: 5′-UGUUUUCACCUCAUAUGCUAU-3′ (SEQ ID NO: 1760)TTR-688 21 nt Target: 5′-GUUUUCACCUCAUAUGCUAUG-3′ (SEQ ID NO: 1761)TTR-689 21 nt Target: 5′-UUUUCACCUCAUAUGCUAUGU-3′ (SEQ ID NO: 1762)TTR-690 21 nt Target: 5′-UUUCACCUCAUAUGCUAUGUU-3′ (SEQ ID NO: 1763)TTR-691 21 nt Target: 5′-UUCACCUCAUAUGCUAUGUUA-3′ (SEQ ID NO: 1764)TTR-692 21 nt Target: 5′-UCACCUCAUAUGCUAUGUUAG-3′ (SEQ ID NO: 1765)TTR-693 21 nt Target: 5′-CACCUCAUAUGCUAUGUUAGA-3′ (SEQ ID NO: 1766)TTR-694 21 nt Target: 5′-ACCUCAUAUGCUAUGUUAGAA-3′ (SEQ ID NO: 1767)TTR-695 21 nt Target: 5′-CCUCAUAUGCUAUGUUAGAAG-3′ (SEQ ID NO: 1768)TTR-696 21 nt Target: 5′-CUCAUAUGCUAUGUUAGAAGU-3′ (SEQ ID NO: 1769)TTR-697 21 nt Target: 5′-UCAUAUGCUAUGUUAGAAGUC-3′ (SEQ ID NO: 1770)TTR-698 21 nt Target: 5′-CAUAUGCUAUGUUAGAAGUCC-3′ (SEQ ID NO: 1771)TTR-699 21 nt Target: 5′-AUAUGCUAUGUUAGAAGUCCA-3′ (SEQ ID NO: 1772)TTR-702 21 nt Target: 5′-UGCUAUGUUAGAAGUCCAGGC-3′ (SEQ ID NO: 1773)TTR-704 21 nt Target: 5′-CUAUGUUAGAAGUCCAGGCAG-3′ (SEQ ID NO: 1774)TTR-705 21 nt Target: 5′-UAUGUUAGAAGUCCAGGCAGA-3′ (SEQ ID NO: 1775)TTR-706 21 nt Target: 5′-AUGUUAGAAGUCCAGGCAGAG-3′ (SEQ ID NO: 1776)TTR-707 21 nt Target: 5′-UGUUAGAAGUCCAGGCAGAGA-3′ (SEQ ID NO: 1777)TTR-708 21 nt Target: 5′-GUUAGAAGUCCAGGCAGAGAC-3′ (SEQ ID NO: 1778)TTR-709 21 nt Target: 5′-UUAGAAGUCCAGGCAGAGACA-3′ (SEQ ID NO: 1779)TTR-710 21 nt Target: 5′-UAGAAGUCCAGGCAGAGACAA-3′ (SEQ ID NO: 1780)TTR-711 21 nt Target: 5′-AGAAGUCCAGGCAGAGACAAU-3′ (SEQ ID NO: 1781)TTR-712 21 nt Target: 5′-GAAGUCCAGGCAGAGACAAUA-3′ (SEQ ID NO: 1782)TTR-713 21 nt Target: 5′-AAGUCCAGGCAGAGACAAUAA-3′ (SEQ ID NO: 1783)TTR-714 21 nt Target: 5′-AGUCCAGGCAGAGACAAUAAA-3′ (SEQ ID NO: 1784)TTR-716 21 nt Target: 5′-UCCAGGCAGAGACAAUAAAAC-3′ (SEQ ID NO: 1785)TTR-717 21 nt Target: 5′-CCAGGCAGAGACAAUAAAACA-3′ (SEQ ID NO: 1786)TTR-718 21 nt Target: 5′-CAGGCAGAGACAAUAAAACAU-3′ (SEQ ID NO: 1787)TTR-719 21 nt Target: 5′-AGGCAGAGACAAUAAAACAUU-3′ (SEQ ID NO: 1788)TTR-720 21 nt Target: 5′-GGCAGAGACAAUAAAACAUUC-3′ (SEQ ID NO: 1789)TTR-721 21 nt Target: 5′-GCAGAGACAAUAAAACAUUCC-3′ (SEQ ID NO: 1790)TTR-722 21 nt Target: 5′-CAGAGACAAUAAAACAUUCCU-3′ (SEQ ID NO: 1791)TTR-723 21 nt Target: 5′-AGAGACAAUAAAACAUUCCUG-3′ (SEQ ID NO: 1792)TTR-724 21 nt Target: 5′-GAGACAAUAAAACAUUCCUGU-3′ (SEQ ID NO: 1793)TTR-725 21 nt Target: 5′-AGACAAUAAAACAUUCCUGUG-3′ (SEQ ID NO: 1794)TTR-726 21 nt Target: 5′-GACAAUAAAACAUUCCUGUGA-3′ (SEQ ID NO: 1795)TTR-727 21 nt Target: 5′-ACAAUAAAACAUUCCUGUGAA-3′ (SEQ ID NO: 1796)TTR-728 21 nt Target: 5′-CAAUAAAACAUUCCUGUGAAA-3′ (SEQ ID NO: 1797)TTR-731 21 nt Target: 5′-UAAAACAUUCCUGUGAAAGGC-3′ (SEQ ID NO: 1798)TTR-732 21 nt Target: 5′-AAAACAUUCCUGUGAAAGGCA-3′ (SEQ ID NO: 1799)TTR-733 21 nt Target: 5′-AAACAUUCCUGUGAAAGGCAC-3′ (SEQ ID NO: 1800)TTR-734 21 nt Target: 5′-AACAUUCCUGUGAAAGGCACU-3′ (SEQ ID NO: 1801)TTR-735 21 nt Target: 5′-ACAUUCCUGUGAAAGGCACUU-3′ (SEQ ID NO: 1802)TTR-736 21 nt Target: 5′-CAUUCCUGUGAAAGGCACUUU-3′ (SEQ ID NO: 1803)TTR-738 21 nt Target: 5′-UUCCUGUGAAAGGCACUUUUC-3′ (SEQ ID NO: 1804)TTR-739 21 nt Target: 5′-UCCUGUGAAAGGCACUUUUCA-3′ (SEQ ID NO: 1805)TTR-740 21 nt Target: 5′-CCUGUGAAAGGCACUUUUCAU-3′ (SEQ ID NO: 1806)TTR-741 21 nt Target: 5′-CUGUGAAAGGCACUUUUCAUU-3′ (SEQ ID NO: 1807)TTR-742 21 nt Target: 5′-UGUGAAAGGCACUUUUCAUUC-3′ (SEQ ID NO: 1808)TTR-743 21 nt Target: 5′-GUGAAAGGCACUUUUCAUUCC-3′ (SEQ ID NO: 1809)TTR-744 21 nt Target: 5′-UGAAAGGCACUUUUCAUUCCA-3′ (SEQ ID NO: 1810)TTR-745 21 nt Target: 5′-GAAAGGCACUUUUCAUUCCAC-3′ (SEQ ID NO: 1811)TTR-746 21 nt Target: 5′-AAAGGCACUUUUCAUUCCACU-3′ (SEQ ID NO: 1812)TTR-747 21 nt Target: 5′-AAGGCACUUUUCAUUCCACUU-3′ (SEQ ID NO: 1813)TTR-748 21 nt Target: 5′-AGGCACUUUUCAUUCCACUUU-3′ (SEQ ID NO: 1814)TTR-749 21 nt Target: 5′-GGCACUUUUCAUUCCACUUUA-3′ (SEQ ID NO: 1815)TTR-750 21 nt Target: 5′-GCACUUUUCAUUCCACUUUAA-3′ (SEQ ID NO: 1816)TTR-751 21 nt Target: 5′-CACUUUUCAUUCCACUUUAAC-3′ (SEQ ID NO: 1817)TTR-752 21 nt Target: 5′-ACUUUUCAUUCCACUUUAACU-3′ (SEQ ID NO: 1818)TTR-753 21 nt Target: 5′-CUUUUCAUUCCACUUUAACUU-3′ (SEQ ID NO: 1819)TTR-754 21 nt Target: 5′-UUUUCAUUCCACUUUAACUUG-3′ (SEQ ID NO: 1820)TTR-755 21 nt Target: 5′-UUUCAUUCCACUUUAACUUGA-3′ (SEQ ID NO: 1821)TTR-756 21 nt Target: 5′-UUCAUUCCACUUUAACUUGAU-3′ (SEQ ID NO: 1822)TTR-757 21 nt Target: 5′-UCAUUCCACUUUAACUUGAUU-3′ (SEQ ID NO: 1823)TTR-758 21 nt Target: 5′-CAUUCCACUUUAACUUGAUUU-3′ (SEQ ID NO: 1824)TTR-759 21 nt Target: 5′-AUUCCACUUUAACUUGAUUUU-3′ (SEQ ID NO: 1825)TTR-760 21 nt Target: 5′-UUCCACUUUAACUUGAUUUUU-3′ (SEQ ID NO: 1826)TTR-761 21 nt Target: 5′-UCCACUUUAACUUGAUUUUUU-3′ (SEQ ID NO: 1827)TTR-762 21 nt Target: 5′-CCACUUUAACUUGAUUUUUUA-3′ (SEQ ID NO: 1828)TTR-763 21 nt Target: 5′-CACUUUAACUUGAUUUUUUAA-3′ (SEQ ID NO: 1829)TTR-764 21 nt Target: 5′-ACUUUAACUUGAUUUUUUAAA-3′ (SEQ ID NO: 1830)TTR-765 21 nt Target: 5′-CUUUAACUUGAUUUUUUAAAU-3′ (SEQ ID NO: 1831)TTR-766 21 nt Target: 5′-UUUAACUUGAUUUUUUAAAUU-3′ (SEQ ID NO: 1832)TTR-767 21 nt Target: 5′-UUAACUUGAUUUUUUAAAUUC-3′ (SEQ ID NO: 1833)TTR-768 21 nt Target: 5′-UAACUUGAUUUUUUAAAUUCC-3′ (SEQ ID NO: 1834)TTR-769 21 nt Target: 5′-AACUUGAUUUUUUAAAUUCCC-3′ (SEQ ID NO: 1835)TTR-770 21 nt Target: 5′-ACUUGAUUUUUUAAAUUCCCU-3′ (SEQ ID NO: 1836)TTR-771 21 nt Target: 5′-CUUGAUUUUUUAAAUUCCCUU-3′ (SEQ ID NO: 1837)TTR-772 21 nt Target: 5′-UUGAUUUUUUAAAUUCCCUUA-3′ (SEQ ID NO: 1838)TTR-773 21 nt Target: 5′-UGAUUUUUUAAAUUCCCUUAU-3′ (SEQ ID NO: 1839)TTR-775 21 nt Target: 5′-AUUUUUUAAAUUCCCUUAUUG-3′ (SEQ ID NO: 1840)TTR-780 21 nt Target: 5′-UUAAAUUCCCUUAUUGUCCCU-3′ (SEQ ID NO: 1841)TTR-781 21 nt Target: 5′-UAAAUUCCCUUAUUGUCCCUU-3′ (SEQ ID NO: 1842)TTR-784 21 nt Target: 5′-AUUCCCUUAUUGUCCCUUCCA-3′ (SEQ ID NO: 1843)TTR-805 21 nt Target: 5′-AAAAAAAGAGAAUCAAAAUUU-3′ (SEQ ID NO: 1844)TTR-806 21 nt Target: 5′-AAAAAAGAGAAUCAAAAUUUU-3′ (SEQ ID NO: 1845)TTR-807 21 nt Target: 5′-AAAAAGAGAAUCAAAAUUUUA-3′ (SEQ ID NO: 1846)TTR-808 21 nt Target: 5′-AAAAGAGAAUCAAAAUUUUAC-3′ (SEQ ID NO: 1847)TTR-809 21 nt Target: 5′-AAAGAGAAUCAAAAUUUUACA-3′ (SEQ ID NO: 1848)TTR-810 21 nt Target: 5′-AAGAGAAUCAAAAUUUUACAA-3′ (SEQ ID NO: 1849)TTR-811 21 nt Target: 5′-AGAGAAUCAAAAUUUUACAAA-3′ (SEQ ID NO: 1850)TTR-812 21 nt Target: 5′-GAGAAUCAAAAUUUUACAAAG-3′ (SEQ ID NO: 1851)TTR-813 21 nt Target: 5′-AGAAUCAAAAUUUUACAAAGA-3′ (SEQ ID NO: 1852)TTR-814 21 nt Target: 5′-GAAUCAAAAUUUUACAAAGAA-3′ (SEQ ID NO: 1853)TTR-815 21 nt Target: 5′-AAUCAAAAUUUUACAAAGAAU-3′ (SEQ ID NO: 1854)TTR-816 21 nt Target: 5′-AUCAAAAUUUUACAAAGAAUC-3′ (SEQ ID NO: 1855)TTR-817 21 nt Target: 5′-UCAAAAUUUUACAAAGAAUCA-3′ (SEQ ID NO: 1856)TTR-818 21 nt Target: 5′-CAAAAUUUUACAAAGAAUCAA-3′ (SEQ ID NO: 1857)TTR-819 21 nt Target: 5′-AAAAUUUUACAAAGAAUCAAA-3′ (SEQ ID NO: 1858)TTR-821 21 nt Target: 5′-AAUUUUACAAAGAAUCAAAGG-3′ (SEQ ID NO: 1859)TTR-822 21 nt Target: 5′-AUUUUACAAAGAAUCAAAGGA-3′ (SEQ ID NO: 1860)TTR-823 21 nt Target: 5′-UUUUACAAAGAAUCAAAGGAA-3′ (SEQ ID NO: 1861)TTR-824 21 nt Target: 5′-UUUACAAAGAAUCAAAGGAAU-3′ (SEQ ID NO: 1862)TTR-825 21 nt Target: 5′-UUACAAAGAAUCAAAGGAAUU-3′ (SEQ ID NO: 1863)TTR-826 21 nt Target: 5′-UACAAAGAAUCAAAGGAAUUC-3′ (SEQ ID NO: 1864)TTR-827 21 nt Target: 5′-ACAAAGAAUCAAAGGAAUUCU-3′ (SEQ ID NO: 1865)TTR-828 21 nt Target: 5′-CAAAGAAUCAAAGGAAUUCUA-3′ (SEQ ID NO: 1866)TTR-829 21 nt Target: 5′-AAAGAAUCAAAGGAAUUCUAG-3′ (SEQ ID NO: 1867)TTR-830 21 nt Target: 5′-AAGAAUCAAAGGAAUUCUAGA-3′ (SEQ ID NO: 1868)TTR-831 21 nt Target: 5′-AGAAUCAAAGGAAUUCUAGAA-3′ (SEQ ID NO: 1869)TTR-832 21 nt Target: 5′-GAAUCAAAGGAAUUCUAGAAA-3′ (SEQ ID NO: 1870)TTR-833 21 nt Target: 5′-AAUCAAAGGAAUUCUAGAAAG-3′ (SEQ ID NO: 1871)TTR-834 21 nt Target: 5′-AUCAAAGGAAUUCUAGAAAGU-3′ (SEQ ID NO: 1872)TTR-835 21 nt Target: 5′-UCAAAGGAAUUCUAGAAAGUA-3′ (SEQ ID NO: 1873)TTR-869 21 nt Target: 5′-CUAGGAGAGAUCCAAAUUUCC-3′ (SEQ ID NO: 1874)TTR-870 21 nt Target: 5′-UAGGAGAGAUCCAAAUUUCCA-3′ (SEQ ID NO: 1875)TTR-873 21 nt Target: 5′-GAGAGAUCCAAAUUUCCAUUG-3′ (SEQ ID NO: 1876)TTR-874 21 nt Target: 5′-AGAGAUCCAAAUUUCCAUUGU-3′ (SEQ ID NO: 1877)TTR-875 21 nt Target: 5′-GAGAUCCAAAUUUCCAUUGUC-3′ (SEQ ID NO: 1878)TTR-876 21 nt Target: 5′-AGAUCCAAAUUUCCAUUGUCU-3′ (SEQ ID NO: 1879)TTR-877 21 nt Target: 5′-GAUCCAAAUUUCCAUUGUCUU-3′ (SEQ ID NO: 1880)TTR-878 21 nt Target: 5′-AUCCAAAUUUCCAUUGUCUUG-3′ (SEQ ID NO: 1881)TTR-879 21 nt Target: 5′-UCCAAAUUUCCAUUGUCUUGC-3′ (SEQ ID NO: 1882)TTR-880 21 nt Target: 5′-CCAAAUUUCCAUUGUCUUGCA-3′ (SEQ ID NO: 1883)TTR-881 21 nt Target: 5′-CAAAUUUCCAUUGUCUUGCAA-3′ (SEQ ID NO: 1884)TTR-882 21 nt Target: 5′-AAAUUUCCAUUGUCUUGCAAG-3′ (SEQ ID NO: 1885)TTR-883 21 nt Target: 5′-AAUUUCCAUUGUCUUGCAAGC-3′ (SEQ ID NO: 1886)TTR-884 21 nt Target: 5′-AUUUCCAUUGUCUUGCAAGCA-3′ (SEQ ID NO: 1887)TTR-885 21 nt Target: 5′-UUUCCAUUGUCUUGCAAGCAA-3′ (SEQ ID NO: 1888)TTR-886 21 nt Target: 5′-UUCCAUUGUCUUGCAAGCAAA-3′ (SEQ ID NO: 1889)TTR-887 21 nt Target: 5′-UCCAUUGUCUUGCAAGCAAAG-3′ (SEQ ID NO: 1890)TTR-888 21 nt Target: 5′-CCAUUGUCUUGCAAGCAAAGC-3′ (SEQ ID NO: 1891)TTR-889 21 nt Target: 5′-CAUUGUCUUGCAAGCAAAGCA-3′ (SEQ ID NO: 1892)TTR-890 21 nt Target: 5′-AUUGUCUUGCAAGCAAAGCAC-3′ (SEQ ID NO: 1893)TTR-891 21 nt Target: 5′-UUGUCUUGCAAGCAAAGCACG-3′ (SEQ ID NO: 1894)TTR-892 21 nt Target: 5′-UGUCUUGCAAGCAAAGCACGU-3′ (SEQ ID NO: 1895)TTR-893 21 nt Target: 5′-GUCUUGCAAGCAAAGCACGUA-3′ (SEQ ID NO: 1896)TTR-894 21 nt Target: 5′-UCUUGCAAGCAAAGCACGUAU-3′ (SEQ ID NO: 1897)TTR-895 21 nt Target: 5′-CUUGCAAGCAAAGCACGUAUU-3′ (SEQ ID NO: 1898)TTR-896 21 nt Target: 5′-UUGCAAGCAAAGCACGUAUUA-3′ (SEQ ID NO: 1899)TTR-897 21 nt Target: 5′-UGCAAGCAAAGCACGUAUUAA-3′ (SEQ ID NO: 1900)TTR-898 21 nt Target: 5′-GCAAGCAAAGCACGUAUUAAA-3′ (SEQ ID NO: 1901)TTR-899 21 nt Target: 5′-CAAGCAAAGCACGUAUUAAAU-3′ (SEQ ID NO: 1902)TTR-900 21 nt Target: 5′-AAGCAAAGCACGUAUUAAAUA-3′ (SEQ ID NO: 1903)TTR-901 21 nt Target: 5′-AGCAAAGCACGUAUUAAAUAU-3′ (SEQ ID NO: 1904)TTR-902 21 nt Target: 5′-GCAAAGCACGUAUUAAAUAUG-3′ (SEQ ID NO: 1905)TTR-903 21 nt Target: 5′-CAAAGCACGUAUUAAAUAUGA-3′ (SEQ ID NO: 1906)TTR-904 21 nt Target: 5′-AAAGCACGUAUUAAAUAUGAU-3′ (SEQ ID NO: 1907)TTR-905 21 nt Target: 5′-AAGCACGUAUUAAAUAUGAUC-3′ (SEQ ID NO: 1908)TTR-906 21 nt Target: 5′-AGCACGUAUUAAAUAUGAUCU-3′ (SEQ ID NO: 1909)TTR-908 21 nt Target: 5′-CACGUAUUAAAUAUGAUCUGC-3′ (SEQ ID NO: 1910)TTR-909 21 nt Target: 5′-ACGUAUUAAAUAUGAUCUGCA-3′ (SEQ ID NO: 1911)TTR-911 21 nt Target: 5′-GUAUUAAAUAUGAUCUGCAGC-3′ (SEQ ID NO: 1912)TTR-912 21 nt Target: 5′-UAUUAAAUAUGAUCUGCAGCC-3′ (SEQ ID NO: 1913)TTR-913 21 nt Target: 5′-AUUAAAUAUGAUCUGCAGCCA-3′ (SEQ ID NO: 1914)TTR-914 21 nt Target: 5′-UUAAAUAUGAUCUGCAGCCAU-3′ (SEQ ID NO: 1915)TTR-915 21 nt Target: 5′-UAAAUAUGAUCUGCAGCCAUU-3′ (SEQ ID NO: 1916)TTR-916 21 nt Target: 5′-AAAUAUGAUCUGCAGCCAUUA-3′ (SEQ ID NO: 1917)TTR-917 21 nt Target: 5′-AAUAUGAUCUGCAGCCAUUAA-3′ (SEQ ID NO: 1918)TTR-918 21 nt Target: 5′-AUAUGAUCUGCAGCCAUUAAA-3′ (SEQ ID NO: 1919)TTR-919 21 nt Target: 5′-UAUGAUCUGCAGCCAUUAAAA-3′ (SEQ ID NO: 1920)

TABLE 5 Selected Human Anti-Transthyretin “Blunt/Blunt” DsiRNAs5′-GUUGACUAAGUCAAUAAUCAGAAUCAG-3′ (SEQ ID NO: 1921)3′-CAACUGAUUCAGUUAUUAGUCUUAGUC-5′ (SEQ ID NO: 385) TTR-27 Target:5′-GTTGACTAAGTCAATAATCAGAATCAG-3′ (SEQ ID NO: 769)5′-UUGACUAAGUCAAUAAUCAGAAUCAGC-3′ (SEQ ID NO: 1922)3′-AACUGAUUCAGUUAUUAGUCUUAGUCG-5′ (SEQ ID NO: 386) TTR-28 Target:5′-TTGACTAAGTCAATAATCAGAATCAGC-3′ (SEQ ID NO: 770)5′-UGACUAAGUCAAUAAUCAGAAUCAGCA-3′ (SEQ ID NO: 1923)3′-ACUGAUUCAGUUAUUAGUCUUAGUCGU-5′ (SEQ ID NO: 387) TTR-29 Target:5′-TGACTAAGTCAATAATCAGAATCAGCA-3′ (SEQ ID NO: 771)5′-GACUAAGUCAAUAAUCAGAAUCAGCAG-3′ (SEQ ID NO: 1924)3′-CUGAUUCAGUUAUUAGUCUUAGUCGUC-5′ (SEQ ID NO: 388) TTR-30 Target:5′-GACTAAGTCAATAATCAGAATCAGCAG-3′ (SEQ ID NO: 772)5′-ACUAAGUCAAUAAUCAGAAUCAGCAGG-3′ (SEQ ID NO: 1925)3′-UGAUUCAGUUAUUAGUCUUAGUCGUCC-5′ (SEQ ID NO: 389) TTR-31 Target:5′-ACTAAGTCAATAATCAGAATCAGCAGG-3′ (SEQ ID NO: 773)5′-CUAAGUCAAUAAUCAGAAUCAGCAGGU-3′ (SEQ ID NO: 1926)3′-GAUUCAGUUAUUAGUCUUAGUCGUCCA-5′ (SEQ ID NO: 390) TTR-32 Target:5′-CTAAGTCAATAATCAGAATCAGCAGGT-3′ (SEQ ID NO: 774)5′-UAAGUCAAUAAUCAGAAUCAGCAGGUU-3′ (SEQ ID NO: 1927)3′-AUUCAGUUAUUAGUCUUAGUCGUCCAA-5′ (SEQ ID NO: 391) TTR-33 Target:5′-TAAGTCAATAATCAGAATCAGCAGGTT-3′ (SEQ ID NO: 775)5′-AAGUCAAUAAUCAGAAUCAGCAGGUUU-3′ (SEQ ID NO: 1928)3′-UUCAGUUAUUAGUCUUAGUCGUCCAAA-5′ (SEQ ID NO: 392) TTR-34 Target:5′-AAGTCAATAATCAGAATCAGCAGGTTT-3′ (SEQ ID NO: 776)5′-AGUCAAUAAUCAGAAUCAGCAGGUUUG-3′ (SEQ ID NO: 1929)3′-UCAGUUAUUAGUCUUAGUCGUCCAAAC-5′ (SEQ ID NO: 393) TTR-35 Target:5′-AGTCAATAATCAGAATCAGCAGGTTTG-3′ (SEQ ID NO: 777)5′-GUCAAUAAUCAGAAUCAGCAGGUUUGC-3′ (SEQ ID NO: 1930)3′-CAGUUAUUAGUCUUAGUCGUCCAAACG-5′ (SEQ ID NO: 394) TTR-36 Target:5′-GTCAATAATCAGAATCAGCAGGTTTGC-3′ (SEQ ID NO: 778)5′-UCAAUAAUCAGAAUCAGCAGGUUUGCA-3′ (SEQ ID NO: 1931)3′-AGUUAUUAGUCUUAGUCGUCCAAACGU-5′ (SEQ ID NO: 395) TTR-37 Target:5′-TCAATAATCAGAATCAGCAGGTTTGCA-3′ (SEQ ID NO: 779)5′-CAAUAAUCAGAAUCAGCAGGUUUGCAG-3′ (SEQ ID NO: 1932)3′-GUUAUUAGUCUUAGUCGUCCAAACGUC-5′ (SEQ ID NO: 396) TTR-38 Target:5′-CAATAATCAGAATCAGCAGGTTTGCAG-3′ (SEQ ID NO: 780)5′-AAUAAUCAGAAUCAGCAGGUUUGCAGU-3′ (SEQ ID NO: 1933)3′-UUAUUAGUCUUAGUCGUCCAAACGUCA-5′ (SEQ ID NO: 397) TTR-39 Target:5′-AATAATCAGAATCAGCAGGTTTGCAGT-3′ (SEQ ID NO: 781)5′-AUAAUCAGAAUCAGCAGGUUUGCAGUC-3′ (SEQ ID NO: 1934)3′-UAUUAGUCUUAGUCGUCCAAACGUCAG-5′ (SEQ ID NO: 398) TTR-40 Target:5′-ATAATCAGAATCAGCAGGTTTGCAGTC-3′ (SEQ ID NO: 782)5′-UAAUCAGAAUCAGCAGGUUUGCAGUCA-3′ (SEQ ID NO: 1935)3′-AUUAGUCUUAGUCGUCCAAACGUCAGU-5′ (SEQ ID NO: 399) TTR-41 Target:5′-TAATCAGAATCAGCAGGTTTGCAGTCA-3′ (SEQ ID NO: 783)5′-AUCAGAAUCAGCAGGUUUGCAGUCAGA-3′ (SEQ ID NO: 1936)3′-UAGUCUUAGUCGUCCAAACGUCAGUCU-5′ (SEQ ID NO: 400) TTR-43 Target:5′-ATCAGAATCAGCAGGTTTGCAGTCAGA-3′ (SEQ ID NO: 784)5′-UCAGAAUCAGCAGGUUUGCAGUCAGAU-3′ (SEQ ID NO: 1937)3′-AGUCUUAGUCGUCCAAACGUCAGUCUA-5′ (SEQ ID NO: 401) TTR-44 Target:5′-TCAGAATCAGCAGGTTTGCAGTCAGAT-3′ (SEQ ID NO: 785)5′-AGAAUCAGCAGGUUUGCAGUCAGAUUG-3′ (SEQ ID NO: 1938)3′-UCUUAGUCGUCCAAACGUCAGUCUAAC-5′ (SEQ ID NO: 402) TTR-46 Target:5′-AGAATCAGCAGGTTTGCAGTCAGATTG-3′ (SEQ ID NO: 786)5′-GAAUCAGCAGGUUUGCAGUCAGAUUGG-3′ (SEQ ID NO: 1939)3′-CUUAGUCGUCCAAACGUCAGUCUAACC-5′ (SEQ ID NO: 403) TTR-47 Target:5′-GAATCAGCAGGTTTGCAGTCAGATTGG-3′ (SEQ ID NO: 787)5′-UUGCAGUCAGAUUGGCAGGGAUAAGCA-3′ (SEQ ID NO: 1940)3′-AACGUCAGUCUAACCGUCCCUAUUCGU-5′ (SEQ ID NO: 404) TTR-59 Target:5′-TTGCAGTCAGATTGGCAGGGATAAGCA-3′ (SEQ ID NO: 788)5′-CAGCCUAGCUCAGGAGAAGUGAGUAUA-3′ (SEQ ID NO: 1941)3′-GUCGGAUCGAGUCCUCUUCACUCAUAU-5′ (SEQ ID NO: 405) TTR-84 Target:5′-CAGCCTAGCTCAGGAGAAGTGAGTATA-3′ (SEQ ID NO: 789)5′-CCUAGCUCAGGAGAAGUGAGUAUAAAA-3′ (SEQ ID NO: 1942)3′-GGAUCGAGUCCUCUUCACUCAUAUUUU-5′ (SEQ ID NO: 406) TTR-87 Target:5′-CCTAGCTCAGGAGAAGTGAGTATAAAA-3′ (SEQ ID NO: 790)5′-CUAGCUCAGGAGAAGUGAGUAUAAAAG-3′ (SEQ ID NO: 1943)3′-GAUCGAGUCCUCUUCACUCAUAUUUUC-5′ (SEQ ID NO: 407) TTR-88 Target:5′-CTAGCTCAGGAGAAGTGAGTATAAAAG-3′ (SEQ ID NO: 791)5′-UAGCUCAGGAGAAGUGAGUAUAAAAGC-3′ (SEQ ID NO: 1944)3′-AUCGAGUCCUCUUCACUCAUAUUUUCG-5′ (SEQ ID NO: 408) TTR-89 Target:5′-TAGCTCAGGAGAAGTGAGTATAAAAGC-3′ (SEQ ID NO: 792)5′-AGCUCAGGAGAAGUGAGUAUAAAAGCC-3′ (SEQ ID NO: 1945)3′-UCGAGUCCUCUUCACUCAUAUUUUCGG-5′ (SEQ ID NO: 409) TTR-90 Target:5′-AGCTCAGGAGAAGTGAGTATAAAAGCC-3′ (SEQ ID NO: 793)5′-CUCAGGAGAAGUGAGUAUAAAAGCCCC-3′ (SEQ ID NO: 1946)3′-GAGUCCUCUUCACUCAUAUUUUCGGGG-5′ (SEQ ID NO: 410) TTR-92 Target:5′-CTCAGGAGAAGTGAGTATAAAAGCCCC-3′ (SEQ ID NO: 794)5′-GAGCAGCCAUCACAGAAGUCCACUCAU-3′ (SEQ ID NO: 1947)3′-CUCGUCGGUAGUGUCUUCAGGUGAGUA-5′ (SEQ ID NO: 411) TTR-126 Target:5′-GAGCAGCCATCACAGAAGTCCACTCAT-3′ (SEQ ID NO: 795)5′-AGCAGCCAUCACAGAAGUCCACUCAUU-3′ (SEQ ID NO: 1948)3′-UCGUCGGUAGUGUCUUCAGGUGAGUAA-5′ (SEQ ID NO: 412) TTR-127 Target:5′-AGCAGCCATCACAGAAGTCCACTCATT-3′ (SEQ ID NO: 796)5′-GCAGCCAUCACAGAAGUCCACUCAUUC-3′ (SEQ ID NO: 1949)3′-CGUCGGUAGUGUCUUCAGGUGAGUAAG-5′ (SEQ ID NO: 413) TTR-128 Target:5′-GCAGCCATCACAGAAGTCCACTCATTC-3′ (SEQ ID NO: 797)5′-CAGCCAUCACAGAAGUCCACUCAUUCU-3′ (SEQ ID NO: 1950)3′-GUCGGUAGUGUCUUCAGGUGAGUAAGA-5′ (SEQ ID NO: 414) TTR-129 Target:5′-CAGCCATCACAGAAGTCCACTCATTCT-3′ (SEQ ID NO: 798)5′-AGCCAUCACAGAAGUCCACUCAUUCUU-3′ (SEQ ID NO: 1951)3′-UCGGUAGUGUCUUCAGGUGAGUAAGAA-5′ (SEQ ID NO: 415) TTR-130 Target:5′-AGCCATCACAGAAGTCCACTCATTCTT-3′ (SEQ ID NO: 799)5′-GCCAUCACAGAAGUCCACUCAUUCUUG-3′ (SEQ ID NO: 1952)3′-CGGUAGUGUCUUCAGGUGAGUAAGAAC-5′ (SEQ ID NO: 416) TTR-131 Target:5′-GCCATCACAGAAGTCCACTCATTCTTG-3′ (SEQ ID NO: 800)5′-CCAUCACAGAAGUCCACUCAUUCUUGG-3′ (SEQ ID NO: 1953)3′-GGUAGUGUCUUCAGGUGAGUAAGAACC-5′ (SEQ ID NO: 417) TTR-132 Target:5′-CCATCACAGAAGTCCACTCATTCTTGG-3′ (SEQ ID NO: 801)5′-AUCACAGAAGUCCACUCAUUCUUGGCA-3′ (SEQ ID NO: 1954)3′-UAGUGUCUUCAGGUGAGUAAGAACCGU-5′ (SEQ ID NO: 418) TTR-134 Target:5′-ATCACAGAAGTCCACTCATTCTTGGCA-3′ (SEQ ID NO: 802)5′-UCACAGAAGUCCACUCAUUCUUGGCAG-3′ (SEQ ID NO: 1955)3′-AGUGUCUUCAGGUGAGUAAGAACCGUC-5′ (SEQ ID NO: 419) TTR-135 Target:5′-TCACAGAAGTCCACTCATTCTTGGCAG-3′ (SEQ ID NO: 803)5′-CAUUCUUGGCAGGAUGGCUUCUCAUCG-3′ (SEQ ID NO: 1956)3′-GUAAGAACCGUCCUACCGAAGAGUAGC-5′ (SEQ ID NO: 420) TTR-150 Target:5′-CATTCTTGGCAGGATGGCTTCTCATCG-3′ (SEQ ID NO: 804)5′-AUUCUUGGCAGGAUGGCUUCUCAUCGU-3′ (SEQ ID NO: 1957)3′-UAAGAACCGUCCUACCGAAGAGUAGCA-5′ (SEQ ID NO: 421) TTR-151 Target:5′-ATTCTTGGCAGGATGGCTTCTCATCGT-3′ (SEQ ID NO: 805)5′-UUCUUGGCAGGAUGGCUUCUCAUCGUC-3′ (SEQ ID NO: 1958)3′-AAGAACCGUCCUACCGAAGAGUAGCAG-5′ (SEQ ID NO: 422) TTR-152 Target:5′-TTCTTGGCAGGATGGCTTCTCATCGTC-3′ (SEQ ID NO: 806)5′-UCUUGGCAGGAUGGCUUCUCAUCGUCU-3′ (SEQ ID NO: 1959)3′-AGAACCGUCCUACCGAAGAGUAGCAGA-5′ (SEQ ID NO: 423) TTR-153 Target:5′-TCTTGGCAGGATGGCTTCTCATCGTCT-3′ (SEQ ID NO: 807)5′-CUUGGCAGGAUGGCUUCUCAUCGUCUG-3′ (SEQ ID NO: 1960)3′-GAACCGUCCUACCGAAGAGUAGCAGAC-5′ (SEQ ID NO: 424) TTR-154 Target:5′-CTTGGCAGGATGGCTTCTCATCGTCTG-3′ (SEQ ID NO: 808)5′-UUGGCAGGAUGGCUUCUCAUCGUCUGC-3′ (SEQ ID NO: 1961)3′-AACCGUCCUACCGAAGAGUAGCAGACG-5′ (SEQ ID NO: 425) TTR-155 Target:5′-TTGGCAGGATGGCTTCTCATCGTCTGC-3′ (SEQ ID NO: 809)5′-UGGCAGGAUGGCUUCUCAUCGUCUGCU-3′ (SEQ ID NO: 1962)3′-ACCGUCCUACCGAAGAGUAGCAGACGA-5′ (SEQ ID NO: 426) TTR-156 Target:5′-TGGCAGGATGGCTTCTCATCGTCTGCT-3′ (SEQ ID NO: 810)5′-GGCAGGAUGGCUUCUCAUCGUCUGCUC-3′ (SEQ ID NO: 1963)3′-CCGUCCUACCGAAGAGUAGCAGACGAG-5′ (SEQ ID NO: 427) TTR-157 Target:5′-GGCAGGATGGCTTCTCATCGTCTGCTC-3′ (SEQ ID NO: 811)5′-GCAGGAUGGCUUCUCAUCGUCUGCUCC-3′ (SEQ ID NO: 1964)3′-CGUCCUACCGAAGAGUAGCAGACGAGG-5′ (SEQ ID NO: 428) TTR-158 Target:5′-GCAGGATGGCTTCTCATCGTCTGCTCC-3′ (SEQ ID NO: 812)5′-CAGGAUGGCUUCUCAUCGUCUGCUCCU-3′ (SEQ ID NO: 1965)3′-GUCCUACCGAAGAGUAGCAGACGAGGA-5′ (SEQ ID NO: 429) TTR-159 Target:5′-CAGGATGGCTTCTCATCGTCTGCTCCT-3′ (SEQ ID NO: 813)5′-AGGAUGGCUUCUCAUCGUCUGCUCCUC-3′ (SEQ ID NO: 1966)3′-UCCUACCGAAGAGUAGCAGACGAGGAG-5′ (SEQ ID NO: 430) TTR-160 Target:5′-AGGATGGCTTCTCATCGTCTGCTCCTC-3′ (SEQ ID NO: 814)5′-GGAUGGCUUCUCAUCGUCUGCUCCUCC-3′ (SEQ ID NO: 1967)3′-CCUACCGAAGAGUAGCAGACGAGGAGG-5′ (SEQ ID NO: 431) TTR-161 Target:5′-GGATGGCTTCTCATCGTCTGCTCCTCC-3′ (SEQ ID NO: 815)5′-GAUGGCUUCUCAUCGUCUGCUCCUCCU-3′ (SEQ ID NO: 1968)3′-CUACCGAAGAGUAGCAGACGAGGAGGA-5′ (SEQ ID NO: 432) TTR-162 Target:5′-GATGGCTTCTCATCGTCTGCTCCTCCT-3′ (SEQ ID NO: 816)5′-AUGGCUUCUCAUCGUCUGCUCCUCCUC-3′ (SEQ ID NO: 1969)3′-UACCGAAGAGUAGCAGACGAGGAGGAG-5′ (SEQ ID NO: 433) TTR-163 Target:5′-ATGGCTTCTCATCGTCTGCTCCTCCTC-3′ (SEQ ID NO: 817)5′-UGGCUUCUCAUCGUCUGCUCCUCCUCU-3′ (SEQ ID NO: 1970)3′-ACCGAAGAGUAGCAGACGAGGAGGAGA-5′ (SEQ ID NO: 434) TTR-164 Target:5′-TGGCTTCTCATCGTCTGCTCCTCCTCT-3′ (SEQ ID NO: 818)5′-GGCUUCUCAUCGUCUGCUCCUCCUCUG-3′ (SEQ ID NO: 1971)3′-CCGAAGAGUAGCAGACGAGGAGGAGAC-5′ (SEQ ID NO: 435) TTR-165 Target:5′-GGCTTCTCATCGTCTGCTCCTCCTCTG-3′ (SEQ ID NO: 819)5′-CCUCUGCCUUGCUGGACUGGUAUUUGU-3′ (SEQ ID NO: 1972)3′-GGAGACGGAACGACCUGACCAUAAACA-5′ (SEQ ID NO: 436) TTR-186 Target:5′-CCTCTGCCTTGCTGGACTGGTATTTGT-3′ (SEQ ID NO: 820)5′-CUCUGCCUUGCUGGACUGGUAUUUGUG-3′ (SEQ ID NO: 1973)3′-GAGACGGAACGACCUGACCAUAAACAC-5′ (SEQ ID NO: 437) TTR-187 Target:5′-CTCTGCCTTGCTGGACTGGTATTTGTG-3′ (SEQ ID NO: 821)5′-CACCGGUGAAUCCAAGUGUCCUCUGAU-3′ (SEQ ID NO: 1974)3′-GUGGCCACUUAGGUUCACAGGAGACUA-5′ (SEQ ID NO: 438) TTR-234 Target:5′-CACCGGTGAATCCAAGTGTCCTCTGAT-3′ (SEQ ID NO: 822)5′-GGUGAAUCCAAGUGUCCUCUGAUGGUC-3′ (SEQ ID NO: 1975)3′-CCACUUAGGUUCACAGGAGACUACCAG-5′ (SEQ ID NO: 439) TTR-238 Target:5′-GGTGAATCCAAGTGTCCTCTGATGGTC-3′ (SEQ ID NO: 823)5′-GUGAAUCCAAGUGUCCUCUGAUGGUCA-3′ (SEQ ID NO: 1976)3′-CACUUAGGUUCACAGGAGACUACCAGU-5′ (SEQ ID NO: 440) TTR-239 Target:5′-GTGAATCCAAGTGTCCTCTGATGGTCA-3′ (SEQ ID NO: 824)5′-UGAAUCCAAGUGUCCUCUGAUGGUCAA-3′ (SEQ ID NO: 1977)3′-ACUUAGGUUCACAGGAGACUACCAGUU-5′ (SEQ ID NO: 441) TTR-240 Target:5′-TGAATCCAAGTGTCCTCTGATGGTCAA-3′ (SEQ ID NO: 825)5′-GAAUCCAAGUGUCCUCUGAUGGUCAAA-3′ (SEQ ID NO: 1978)3′-CUUAGGUUCACAGGAGACUACCAGUUU-5′ (SEQ ID NO: 442) TTR-241 Target:5′-GAATCCAAGTGTCCTCTGATGGTCAAA-3′ (SEQ ID NO: 826)5′-AAUCCAAGUGUCCUCUGAUGGUCAAAG-3′ (SEQ ID NO: 1979)3′-UUAGGUUCACAGGAGACUACCAGUUUC-5′ (SEQ ID NO: 443) TTR-242 Target:5′-AATCCAAGTGTCCTCTGATGGTCAAAG-3′ (SEQ ID NO: 827)5′-AUCCAAGUGUCCUCUGAUGGUCAAAGU-3′ (SEQ ID NO: 1980)3′-UAGGUUCACAGGAGACUACCAGUUUCA-5′ (SEQ ID NO: 444) TTR-243 Target:5′-ATCCAAGTGTCCTCTGATGGTCAAAGT-3′ (SEQ ID NO: 828)5′-UCCAAGUGUCCUCUGAUGGUCAAAGUU-3′ (SEQ ID NO: 1981)3′-AGGUUCACAGGAGACUACCAGUUUCAA-5′ (SEQ ID NO: 445) TTR-244 Target:5′-TCCAAGTGTCCTCTGATGGTCAAAGTT-3′ (SEQ ID NO: 829)5′-CCAAGUGUCCUCUGAUGGUCAAAGUUC-3′ (SEQ ID NO: 1982)3′-GGUUCACAGGAGACUACCAGUUUCAAG-5′ (SEQ ID NO: 446) TTR-245 Target:5′-CCAAGTGTCCTCTGATGGTCAAAGTTC-3′ (SEQ ID NO: 830)5′-CAAGUGUCCUCUGAUGGUCAAAGUUCU-3′ (SEQ ID NO: 1983)3′-GUUCACAGGAGACUACCAGUUUCAAGA-5′ (SEQ ID NO: 447) TTR-246 Target:5′-CAAGTGTCCTCTGATGGTCAAAGTTCT-3′ (SEQ ID NO: 831)5′-AAGUGUCCUCUGAUGGUCAAAGUUCUA-3′ (SEQ ID NO: 1984)3′-UUCACAGGAGACUACCAGUUUCAAGAU-5′ (SEQ ID NO: 448) TTR-247 Target:5′-AAGTGTCCTCTGATGGTCAAAGTTCTA-3′ (SEQ ID NO: 832)5′-AGUGUCCUCUGAUGGUCAAAGUUCUAG-3′ (SEQ ID NO: 1985)3′-UCACAGGAGACUACCAGUUUCAAGAUC-5′ (SEQ ID NO: 449) TTR-248 Target:5′-AGTGTCCTCTGATGGTCAAAGTTCTAG-3′ (SEQ ID NO: 833)5′-GUGUCCUCUGAUGGUCAAAGUUCUAGA-3′ (SEQ ID NO: 1986)3′-CACAGGAGACUACCAGUUUCAAGAUCU-5′ (SEQ ID NO: 450) TTR-249 Target:5′-GTGTCCTCTGATGGTCAAAGTTCTAGA-3′ (SEQ ID NO: 834)5′-UGUCCUCUGAUGGUCAAAGUUCUAGAU-3′ (SEQ ID NO: 1987)3′-ACAGGAGACUACCAGUUUCAAGAUCUA-5′ (SEQ ID NO: 451) TTR-250 Target:5′-TGTCCTCTGATGGTCAAAGTTCTAGAT-3′ (SEQ ID NO: 835)5′-GUCCUCUGAUGGUCAAAGUUCUAGAUG-3′ (SEQ ID NO: 1988)3′-CAGGAGACUACCAGUUUCAAGAUCUAC-5′ (SEQ ID NO: 452) TTR-251 Target:5′-GTCCTCTGATGGTCAAAGTTCTAGATG-3′ (SEQ ID NO: 836)5′-UCCUCUGAUGGUCAAAGUUCUAGAUGC-3′ (SEQ ID NO: 1989)3′-AGGAGACUACCAGUUUCAAGAUCUACG-5′ (SEQ ID NO: 453) TTR-252 Target:5′-TCCTCTGATGGTCAAAGTTCTAGATGC-3′ (SEQ ID NO: 837)5′-CCUCUGAUGGUCAAAGUUCUAGAUGCU-3′ (SEQ ID NO: 1990)3′-GGAGACUACCAGUUUCAAGAUCUACGA-5′ (SEQ ID NO: 454) TTR-253 Target:5′-CCTCTGATGGTCAAAGTTCTAGATGCT-3′ (SEQ ID NO: 838)5′-CUCUGAUGGUCAAAGUUCUAGAUGCUG-3′ (SEQ ID NO: 1991)3′-GAGACUACCAGUUUCAAGAUCUACGAC-5′ (SEQ ID NO: 455) TTR-254 Target:5′-CTCTGATGGTCAAAGTTCTAGATGCTG-3′ (SEQ ID NO: 839)5′-UCUGAUGGUCAAAGUUCUAGAUGCUGU-3′ (SEQ ID NO: 1992)3′-AGACUACCAGUUUCAAGAUCUACGACA-5′ (SEQ ID NO: 456) TTR-255 Target:5′-TCTGATGGTCAAAGTTCTAGATGCTGT-3′ (SEQ ID NO: 840)5′-CUGAUGGUCAAAGUUCUAGAUGCUGUC-3′ (SEQ ID NO: 1993)3′-GACUACCAGUUUCAAGAUCUACGACAG-5′ (SEQ ID NO: 457) TTR-256 Target:5′-CTGATGGTCAAAGTTCTAGATGCTGTC-3′ (SEQ ID NO: 841)5′-UGAUGGUCAAAGUUCUAGAUGCUGUCC-3′ (SEQ ID NO: 1994)3′-ACUACCAGUUUCAAGAUCUACGACAGG-5′ (SEQ ID NO: 458) TTR-257 Target:5′-TGATGGTCAAAGTTCTAGATGCTGTCC-3′ (SEQ ID NO: 842)5′-GAUGGUCAAAGUUCUAGAUGCUGUCCG-3′ (SEQ ID NO: 1995)3′-CUACCAGUUUCAAGAUCUACGACAGGC-5′ (SEQ ID NO: 459) TTR-258 Target:5′-GATGGTCAAAGTTCTAGATGCTGTCCG-3′ (SEQ ID NO: 843)5′-GAGCCAUUUGCCUCUGGGAAAACCAGU-3′ (SEQ ID NO: 1996)3′-CUCGGUAAACGGAGACCCUUUUGGUCA-5′ (SEQ ID NO: 460) TTR-346 Target:5′-GAGCCATTTGCCTCTGGGAAAACCAGT-3′ (SEQ ID NO: 844)5′-AGCCAUUUGCCUCUGGGAAAACCAGUG-3′ (SEQ ID NO: 1997)3′-UCGGUAAACGGAGACCCUUUUGGUCAC-5′ (SEQ ID NO: 461) TTR-347 Target:5′-AGCCATTTGCCTCTGGGAAAACCAGTG-3′ (SEQ ID NO: 845)5′-GCCAUUUGCCUCUGGGAAAACCAGUGA-3′ (SEQ ID NO: 1998)3′-CGGUAAACGGAGACCCUUUUGGUCACU-5′ (SEQ ID NO: 462) TTR-348 Target:5′-GCCATTTGCCTCTGGGAAAACCAGTGA-3′ (SEQ ID NO: 846)5′-CCAUUUGCCUCUGGGAAAACCAGUGAG-3′ (SEQ ID NO: 1999)3′-GGUAAACGGAGACCCUUUUGGUCACUC-5′ (SEQ ID NO: 463) TTR-349 Target:5′-CCATTTGCCTCTGGGAAAACCAGTGAG-3′ (SEQ ID NO: 847)5′-CAUUUGCCUCUGGGAAAACCAGUGAGU-3′ (SEQ ID NO: 2000)3′-GUAAACGGAGACCCUUUUGGUCACUCA-5′ (SEQ ID NO: 464) TTR-350 Target:5′-CATTTGCCTCTGGGAAAACCAGTGAGT-3′ (SEQ ID NO: 848)5′-AUUUGCCUCUGGGAAAACCAGUGAGUC-3′ (SEQ ID NO: 2001)3′-UAAACGGAGACCCUUUUGGUCACUCAG-5′ (SEQ ID NO: 465) TTR-351 Target:5′-ATTTGCCTCTGGGAAAACCAGTGAGTC-3′ (SEQ ID NO: 849)5′-UUUGCCUCUGGGAAAACCAGUGAGUCU-3′ (SEQ ID NO: 2002)3′-AAACGGAGACCCUUUUGGUCACUCAGA-5′ (SEQ ID NO: 466) TTR-352 Target:5′-TTTGCCTCTGGGAAAACCAGTGAGTCT-3′ (SEQ ID NO: 850)5′-UUGCCUCUGGGAAAACCAGUGAGUCUG-3′ (SEQ ID NO: 2003)3′-AACGGAGACCCUUUUGGUCACUCAGAC-5′ (SEQ ID NO: 467) TTR-353 Target:5′-TTGCCTCTGGGAAAACCAGTGAGTCTG-3′ (SEQ ID NO: 851)5′-UGCCUCUGGGAAAACCAGUGAGUCUGG-3′ (SEQ ID NO: 2004)3′-ACGGAGACCCUUUUGGUCACUCAGACC-5′ (SEQ ID NO: 468) TTR-354 Target:5′-TGCCTCTGGGAAAACCAGTGAGTCTGG-3′ (SEQ ID NO: 852)5′-GCCUCUGGGAAAACCAGUGAGUCUGGA-3′ (SEQ ID NO: 2005)3′-CGGAGACCCUUUUGGUCACUCAGACCU-5′ (SEQ ID NO: 469) TTR-355 Target:5′-GCCTCTGGGAAAACCAGTGAGTCTGGA-3′ (SEQ ID NO: 853)5′-CCUCUGGGAAAACCAGUGAGUCUGGAG-3′ (SEQ ID NO: 2006)3′-GGAGACCCUUUUGGUCACUCAGACCUC-5′ (SEQ ID NO: 470) TTR-356 Target:5′-CCTCTGGGAAAACCAGTGAGTCTGGAG-3′ (SEQ ID NO: 854)5′-CUCUGGGAAAACCAGUGAGUCUGGAGA-3′ (SEQ ID NO: 2007)3′-GAGACCCUUUUGGUCACUCAGACCUCU-5′ (SEQ ID NO: 471) TTR-357 Target:5′-CTCTGGGAAAACCAGTGAGTCTGGAGA-3′ (SEQ ID NO: 855)5′-UCUGGGAAAACCAGUGAGUCUGGAGAG-3′ (SEQ ID NO: 2008)3′-AGACCCUUUUGGUCACUCAGACCUCUC-5′ (SEQ ID NO: 472) TTR-358 Target:5′-TCTGGGAAAACCAGTGAGTCTGGAGAG-3′ (SEQ ID NO: 856)5′-CUGGGAAAACCAGUGAGUCUGGAGAGC-3′ (SEQ ID NO: 2009)3′-GACCCUUUUGGUCACUCAGACCUCUCG-5′ (SEQ ID NO: 473) TTR-359 Target:5′-CTGGGAAAACCAGTGAGTCTGGAGAGC-3′ (SEQ ID NO: 857)5′-UGGGAAAACCAGUGAGUCUGGAGAGCU-3′ (SEQ ID NO: 2010)3′-ACCCUUUUGGUCACUCAGACCUCUCGA-5′ (SEQ ID NO: 474) TTR-360 Target:5′-TGGGAAAACCAGTGAGTCTGGAGAGCT-3′ (SEQ ID NO: 858)5′-GGGAAAACCAGUGAGUCUGGAGAGCUG-3′ (SEQ ID NO: 2011)3′-CCCUUUUGGUCACUCAGACCUCUCGAC-5′ (SEQ ID NO: 475) TTR-361 Target:5′-GGGAAAACCAGTGAGTCTGGAGAGCTG-3′ (SEQ ID NO: 859)5′-AGAGCUGCAUGGGCUCACAACUGAGGA-3′ (SEQ ID NO: 2012)3′-UCUCGACGUACCCGAGUGUUGACUCCU-5′ (SEQ ID NO: 476) TTR-381 Target:5′-AGAGCTGCATGGGCTCACAACTGAGGA-3′ (SEQ ID NO: 860)5′-GAGCUGCAUGGGCUCACAACUGAGGAG-3′ (SEQ ID NO: 2013)3′-CUCGACGUACCCGAGUGUUGACUCCUC-5′ (SEQ ID NO: 477) TTR-382 Target:5′-GAGCTGCATGGGCTCACAACTGAGGAG-3′ (SEQ ID NO: 861)5′-AGCUGCAUGGGCUCACAACUGAGGAGG-3′ (SEQ ID NO: 2014)3′-UCGACGUACCCGAGUGUUGACUCCUCC-5′ (SEQ ID NO: 478) TTR-383 Target:5′-AGCTGCATGGGCTCACAACTGAGGAGG-3′ (SEQ ID NO: 862)5′-GCUGCAUGGGCUCACAACUGAGGAGGA-3′ (SEQ ID NO: 2015)3′-CGACGUACCCGAGUGUUGACUCCUCCU-5′ (SEQ ID NO: 479) TTR-384 Target:5′-GCTGCATGGGCTCACAACTGAGGAGGA-3′ (SEQ ID NO: 863)5′-CUGCAUGGGCUCACAACUGAGGAGGAA-3′ (SEQ ID NO: 2016)3′-GACGUACCCGAGUGUUGACUCCUCCUU-5′ (SEQ ID NO: 480) TTR-385 Target:5′-CTGCATGGGCTCACAACTGAGGAGGAA-3′ (SEQ ID NO: 864)5′-UGCAUGGGCUCACAACUGAGGAGGAAU-3′ (SEQ ID NO: 2017)3′-ACGUACCCGAGUGUUGACUCCUCCUUA-5′ (SEQ ID NO: 481) TTR-386 Target:5′-TGCATGGGCTCACAACTGAGGAGGAAT-3′ (SEQ ID NO: 865)5′-GCAUGGGCUCACAACUGAGGAGGAAUU-3′ (SEQ ID NO: 2018)3′-CGUACCCGAGUGUUGACUCCUCCUUAA-5′ (SEQ ID NO: 482) TTR-387 Target:5′-GCATGGGCTCACAACTGAGGAGGAATT-3′ (SEQ ID NO: 866)5′-CAUGGGCUCACAACUGAGGAGGAAUUU-3′ (SEQ ID NO: 2019)3′-GUACCCGAGUGUUGACUCCUCCUUAAA-5′ (SEQ ID NO: 483) TTR-388 Target:5′-CATGGGCTCACAACTGAGGAGGAATTT-3′ (SEQ ID NO: 867)5′-AUGGGCUCACAACUGAGGAGGAAUUUG-3′ (SEQ ID NO: 2020)3′-UACCCGAGUGUUGACUCCUCCUUAAAC-5′ (SEQ ID NO: 484) TTR-389 Target:5′-ATGGGCTCACAACTGAGGAGGAATTTG-3′ (SEQ ID NO: 868)5′-UGGGCUCACAACUGAGGAGGAAUUUGU-3′ (SEQ ID NO: 2021)3′-ACCCGAGUGUUGACUCCUCCUUAAACA-5′ (SEQ ID NO: 485) TTR-390 Target:5′-TGGGCTCACAACTGAGGAGGAATTTGT-3′ (SEQ ID NO: 869)5′-GGGCUCACAACUGAGGAGGAAUUUGUA-3′ (SEQ ID NO: 2022)3′-CCCGAGUGUUGACUCCUCCUUAAACAU-5′ (SEQ ID NO: 486) TTR-391 Target:5′-GGGCTCACAACTGAGGAGGAATTTGTA-3′ (SEQ ID NO: 870)5′-GGCUCACAACUGAGGAGGAAUUUGUAG-3′ (SEQ ID NO: 2023)3′-CCGAGUGUUGACUCCUCCUUAAACAUC-5′ (SEQ ID NO: 487) TTR-392 Target:5′-GGCTCACAACTGAGGAGGAATTTGTAG-3′ (SEQ ID NO: 871)5′-GCUCACAACUGAGGAGGAAUUUGUAGA-3′ (SEQ ID NO: 2024)3′-CGAGUGUUGACUCCUCCUUAAACAUCU-5′ (SEQ ID NO: 488) TTR-393 Target:5′-GCTCACAACTGAGGAGGAATTTGTAGA-3′ (SEQ ID NO: 872)5′-CUCACAACUGAGGAGGAAUUUGUAGAA-3′ (SEQ ID NO: 2025)3′-GAGUGUUGACUCCUCCUUAAACAUCUU-5′ (SEQ ID NO: 489) TTR-394 Target:5′-CTCACAACTGAGGAGGAATTTGTAGAA-3′ (SEQ ID NO: 873)5′-UCACAACUGAGGAGGAAUUUGUAGAAG-3′ (SEQ ID NO: 2026)3′-AGUGUUGACUCCUCCUUAAACAUCUUC-5′ (SEQ ID NO: 490) TTR-395 Target:5′-TCACAACTGAGGAGGAATTTGTAGAAG-3′ (SEQ ID NO: 874)5′-CACAACUGAGGAGGAAUUUGUAGAAGG-3′ (SEQ ID NO: 2027)3′-GUGUUGACUCCUCCUUAAACAUCUUCC-5′ (SEQ ID NO: 491) TTR-396 Target:5′-CACAACTGAGGAGGAATTTGTAGAAGG-3′ (SEQ ID NO: 875)5′-CAACUGAGGAGGAAUUUGUAGAAGGGA-3′ (SEQ ID NO: 2028)3′-GUUGACUCCUCCUUAAACAUCUUCCCU-5′ (SEQ ID NO: 492) TTR-398 Target:5′-CAACTGAGGAGGAATTTGTAGAAGGGA-3′ (SEQ ID NO: 876)5′-AACUGAGGAGGAAUUUGUAGAAGGGAU-3′ (SEQ ID NO: 2029)3′-UUGACUCCUCCUUAAACAUCUUCCCUA-5′ (SEQ ID NO: 493) TTR-399 Target:5′-AACTGAGGAGGAATTTGTAGAAGGGAT-3′ (SEQ ID NO: 877)5′-ACUGAGGAGGAAUUUGUAGAAGGGAUA-3′ (SEQ ID NO: 2030)3′-UGACUCCUCCUUAAACAUCUUCCCUAU-5′ (SEQ ID NO: 494) TTR-400 Target:5′-ACTGAGGAGGAATTTGTAGAAGGGATA-3′ (SEQ ID NO: 878)5′-CUGAGGAGGAAUUUGUAGAAGGGAUAU-3′ (SEQ ID NO: 2031)3′-GACUCCUCCUUAAACAUCUUCCCUAUA-5′ (SEQ ID NO: 495) TTR-401 Target:5′-CTGAGGAGGAATTTGTAGAAGGGATAT-3′ (SEQ ID NO: 879)5′-UGAGGAGGAAUUUGUAGAAGGGAUAUA-3′ (SEQ ID NO: 2032)3′-ACUCCUCCUUAAACAUCUUCCCUAUAU-5′ (SEQ ID NO: 496) TTR-402 Target:5′-TGAGGAGGAATTTGTAGAAGGGATATA-3′ (SEQ ID NO: 880)5′-GAGGAGGAAUUUGUAGAAGGGAUAUAC-3′ (SEQ ID NO: 2033)3′-CUCCUCCUUAAACAUCUUCCCUAUAUG-5′ (SEQ ID NO: 497) TTR-403 Target:5′-GAGGAGGAATTTGTAGAAGGGATATAC-3′ (SEQ ID NO: 881)5′-AGGAGGAAUUUGUAGAAGGGAUAUACA-3′ (SEQ ID NO: 2034)3′-UCCUCCUUAAACAUCUUCCCUAUAUGU-5′ (SEQ ID NO: 498) TTR-404 Target:5′-AGGAGGAATTTGTAGAAGGGATATACA-3′ (SEQ ID NO: 882)5′-GGAGGAAUUUGUAGAAGGGAUAUACAA-3′ (SEQ ID NO: 2035)3′-CCUCCUUAAACAUCUUCCCUAUAUGUU-5′ (SEQ ID NO: 499) TTR-405 Target:5′-GGAGGAATTTGTAGAAGGGATATACAA-3′ (SEQ ID NO: 883)5′-GAGGAAUUUGUAGAAGGGAUAUACAAA-3′ (SEQ ID NO: 2036)3′-CUCCUUAAACAUCUUCCCUAUAUGUUU-5′ (SEQ ID NO: 500) TTR-406 Target:5′-GAGGAATTTGTAGAAGGGATATACAAA-3′ (SEQ ID NO: 884)5′-AGGAAUUUGUAGAAGGGAUAUACAAAG-3′ (SEQ ID NO: 2037)3′-UCCUUAAACAUCUUCCCUAUAUGUUUC-5′ (SEQ ID NO: 501) TTR-407 Target:5′-AGGAATTTGTAGAAGGGATATACAAAG-3′ (SEQ ID NO: 885)5′-GGAAUUUGUAGAAGGGAUAUACAAAGU-3′ (SEQ ID NO: 2038)3′-CCUUAAACAUCUUCCCUAUAUGUUUCA-5′ (SEQ ID NO: 502) TTR-408 Target:5′-GGAATTTGTAGAAGGGATATACAAAGT-3′ (SEQ ID NO: 886)5′-GAAUUUGUAGAAGGGAUAUACAAAGUG-3′ (SEQ ID NO: 2039)3′-CUUAAACAUCUUCCCUAUAUGUUUCAC-5′ (SEQ ID NO: 503) TTR-409 Target:5′-GAATTTGTAGAAGGGATATACAAAGTG-3′ (SEQ ID NO: 887)5′-AAUUUGUAGAAGGGAUAUACAAAGUGG-3′ (SEQ ID NO: 2040)3′-UUAAACAUCUUCCCUAUAUGUUUCACC-5′ (SEQ ID NO: 504) TTR-410 Target:5′-AATTTGTAGAAGGGATATACAAAGTGG-3′ (SEQ ID NO: 888)5′-AUUUGUAGAAGGGAUAUACAAAGUGGA-3′ (SEQ ID NO: 2041)3′-UAAACAUCUUCCCUAUAUGUUUCACCU-5′ (SEQ ID NO: 505) TTR-411 Target:5′-ATTTGTAGAAGGGATATACAAAGTGGA-3′ (SEQ ID NO: 889)5′-UUUGUAGAAGGGAUAUACAAAGUGGAA-3′ (SEQ ID NO: 2042)3′-AAACAUCUUCCCUAUAUGUUUCACCUU-5′ (SEQ ID NO: 506) TTR-412 Target:5′-TTTGTAGAAGGGATATACAAAGTGGAA-3′ (SEQ ID NO: 890)5′-UUGUAGAAGGGAUAUACAAAGUGGAAA-3′ (SEQ ID NO: 2043)3′-AACAUCUUCCCUAUAUGUUUCACCUUU-5′ (SEQ ID NO: 507) TTR-413 Target:5′-TTGTAGAAGGGATATACAAAGTGGAAA-3′ (SEQ ID NO: 891)5′-UGUAGAAGGGAUAUACAAAGUGGAAAU-3′ (SEQ ID NO: 2044)3′-ACAUCUUCCCUAUAUGUUUCACCUUUA-5′ (SEQ ID NO: 508) TTR-414 Target:5′-TGTAGAAGGGATATACAAAGTGGAAAT-3′ (SEQ ID NO: 892)5′-GUAGAAGGGAUAUACAAAGUGGAAAUA-3′ (SEQ ID NO: 2045)3′-CAUCUUCCCUAUAUGUUUCACCUUUAU-5′ (SEQ ID NO: 509) TTR-415 Target:5′-GTAGAAGGGATATACAAAGTGGAAATA-3′ (SEQ ID NO: 893)5′-UAGAAGGGAUAUACAAAGUGGAAAUAG-3′ (SEQ ID NO: 2046)3′-AUCUUCCCUAUAUGUUUCACCUUUAUC-5′ (SEQ ID NO: 510) TTR-416 Target:5′-TAGAAGGGATATACAAAGTGGAAATAG-3′ (SEQ ID NO: 894)5′-AGAAGGGAUAUACAAAGUGGAAAUAGA-3′ (SEQ ID NO: 2047)3′-UCUUCCCUAUAUGUUUCACCUUUAUCU-5′ (SEQ ID NO: 511) TTR-417 Target:5′-AGAAGGGATATACAAAGTGGAAATAGA-3′ (SEQ ID NO: 895)5′-GAAGGGAUAUACAAAGUGGAAAUAGAC-3′ (SEQ ID NO: 2048)3′-CUUCCCUAUAUGUUUCACCUUUAUCUG-5′ (SEQ ID NO: 512) TTR-418 Target:5′-GAAGGGATATACAAAGTGGAAATAGAC-3′ (SEQ ID NO: 896)5′-AAGGGAUAUACAAAGUGGAAAUAGACA-3′ (SEQ ID NO: 2049)3′-UUCCCUAUAUGUUUCACCUUUAUCUGU-5′ (SEQ ID NO: 513) TTR-419 Target:5′-AAGGGATATACAAAGTGGAAATAGACA-3′ (SEQ ID NO: 897)5′-AGGGAUAUACAAAGUGGAAAUAGACAC-3′ (SEQ ID NO: 2050)3′-UCCCUAUAUGUUUCACCUUUAUCUGUG-5′ (SEQ ID NO: 514) TTR-420 Target:5′-AGGGATATACAAAGTGGAAATAGACAC-3′ (SEQ ID NO: 898)5′-GGGAUAUACAAAGUGGAAAUAGACACC-3′ (SEQ ID NO: 2051)3′-CCCUAUAUGUUUCACCUUUAUCUGUGG-5′ (SEQ ID NO: 515) TTR-421 Target:5′-GGGATATACAAAGTGGAAATAGACACC-3′ (SEQ ID NO: 899)5′-GGAUAUACAAAGUGGAAAUAGACACCA-3′ (SEQ ID NO: 2052)3′-CCUAUAUGUUUCACCUUUAUCUGUGGU-5′ (SEQ ID NO: 516) TTR-422 Target:5′-GGATATACAAAGTGGAAATAGACACCA-3′ (SEQ ID NO: 900)5′-GAUAUACAAAGUGGAAAUAGACACCAA-3′ (SEQ ID NO: 2053)3′-CUAUAUGUUUCACCUUUAUCUGUGGUU-5′ (SEQ ID NO: 517) TTR-423 Target:5′-GATATACAAAGTGGAAATAGACACCAA-3′ (SEQ ID NO: 901)5′-AUAUACAAAGUGGAAAUAGACACCAAA-3′ (SEQ ID NO: 2054)3′-UAUAUGUUUCACCUUUAUCUGUGGUUU-5′ (SEQ ID NO: 518) TTR-424 Target:5′-ATATACAAAGTGGAAATAGACACCAAA-3′ (SEQ ID NO: 902)5′-UAUACAAAGUGGAAAUAGACACCAAAU-3′ (SEQ ID NO: 2055)3′-AUAUGUUUCACCUUUAUCUGUGGUUUA-5′ (SEQ ID NO: 519) TTR-425 Target:5′-TATACAAAGTGGAAATAGACACCAAAT-3′ (SEQ ID NO: 903)5′-AUACAAAGUGGAAAUAGACACCAAAUC-3′ (SEQ ID NO: 2056)3′-UAUGUUUCACCUUUAUCUGUGGUUUAG-5′ (SEQ ID NO: 520) TTR-426 Target:5′-ATACAAAGTGGAAATAGACACCAAATC-3′ (SEQ ID NO: 904)5′-UACAAAGUGGAAAUAGACACCAAAUCU-3′ (SEQ ID NO: 2057)3′-AUGUUUCACCUUUAUCUGUGGUUUAGA-5′ (SEQ ID NO: 521) TTR-427 Target:5′-TACAAAGTGGAAATAGACACCAAATCT-3′ (SEQ ID NO: 905)5′-ACAAAGUGGAAAUAGACACCAAAUCUU-3′ (SEQ ID NO: 2058)3′-UGUUUCACCUUUAUCUGUGGUUUAGAA-5′ (SEQ ID NO: 522) TTR-428 Target:5′-ACAAAGTGGAAATAGACACCAAATCTT-3′ (SEQ ID NO: 906)5′-CAAAGUGGAAAUAGACACCAAAUCUUA-3′ (SEQ ID NO: 2059)3′-GUUUCACCUUUAUCUGUGGUUUAGAAU-5′ (SEQ ID NO: 523) TTR-429 Target:5′-CAAAGTGGAAATAGACACCAAATCTTA-3′ (SEQ ID NO: 907)5′-AAAGUGGAAAUAGACACCAAAUCUUAC-3′ (SEQ ID NO: 2060)3′-UUUCACCUUUAUCUGUGGUUUAGAAUG-5′ (SEQ ID NO: 524) TTR-430 Target:5′-AAAGTGGAAATAGACACCAAATCTTAC-3′ (SEQ ID NO: 908)5′-AAGUGGAAAUAGACACCAAAUCUUACU-3′ (SEQ ID NO: 2061)3′-UUCACCUUUAUCUGUGGUUUAGAAUGA-5′ (SEQ ID NO: 525) TTR-431 Target:5′-AAGTGGAAATAGACACCAAATCTTACT-3′ (SEQ ID NO: 909)5′-AGUGGAAAUAGACACCAAAUCUUACUG-3′ (SEQ ID NO: 2062)3′-UCACCUUUAUCUGUGGUUUAGAAUGAC-5′ (SEQ ID NO: 526) TTR-432 Target:5′-AGTGGAAATAGACACCAAATCTTACTG-3′ (SEQ ID NO: 910)5′-GUGGAAAUAGACACCAAAUCUUACUGG-3′ (SEQ ID NO: 2063)3′-CACCUUUAUCUGUGGUUUAGAAUGACC-5′ (SEQ ID NO: 527) TTR-433 Target:5′-GTGGAAATAGACACCAAATCTTACTGG-3′ (SEQ ID NO: 911)5′-UGGAAAUAGACACCAAAUCUUACUGGA-3′ (SEQ ID NO: 2064)3′-ACCUUUAUCUGUGGUUUAGAAUGACCU-5′ (SEQ ID NO: 528) TTR-434 Target:5′-TGGAAATAGACACCAAATCTTACTGGA-3′ (SEQ ID NO: 912)5′-GGAAAUAGACACCAAAUCUUACUGGAA-3′ (SEQ ID NO: 2065)3′-CCUUUAUCUGUGGUUUAGAAUGACCUU-5′ (SEQ ID NO: 529) TTR-435 Target:5′-GGAAATAGACACCAAATCTTACTGGAA-3′ (SEQ ID NO: 913)5′-GAAAUAGACACCAAAUCUUACUGGAAG-3′ (SEQ ID NO: 2066)3′-CUUUAUCUGUGGUUUAGAAUGACCUUC-5′ (SEQ ID NO: 530) TTR-436 Target:5′-GAAATAGACACCAAATCTTACTGGAAG-3′ (SEQ ID NO: 914)5′-AAAUAGACACCAAAUCUUACUGGAAGG-3′ (SEQ ID NO: 2067)3′-UUUAUCUGUGGUUUAGAAUGACCUUCC-5′ (SEQ ID NO: 531) TTR-437 Target:5′-AAATAGACACCAAATCTTACTGGAAGG-3′ (SEQ ID NO: 915)5′-AUAGACACCAAAUCUUACUGGAAGGCA-3′ (SEQ ID NO: 2068)3′-UAUCUGUGGUUUAGAAUGACCUUCCGU-5′ (SEQ ID NO: 532) TTR-439 Target:5′-ATAGACACCAAATCTTACTGGAAGGCA-3′ (SEQ ID NO: 916)5′-UAGACACCAAAUCUUACUGGAAGGCAC-3′ (SEQ ID NO: 2069)3′-AUCUGUGGUUUAGAAUGACCUUCCGUG-5′ (SEQ ID NO: 533) TTR-440 Target:5′-TAGACACCAAATCTTACTGGAAGGCAC-3′ (SEQ ID NO: 917)5′-GGCACUUGGCAUCUCCCCAUUCCAUGA-3′ (SEQ ID NO: 2070)3′-CCGUGAACCGUAGAGGGGUAAGGUACU-5′ (SEQ ID NO: 534) TTR-462 Target:5′-GGCACTTGGCATCTCCCCATTCCATGA-3′ (SEQ ID NO: 918)5′-GCACUUGGCAUCUCCCCAUUCCAUGAG-3′ (SEQ ID NO: 2071)3′-CGUGAACCGUAGAGGGGUAAGGUACUC-5′ (SEQ ID NO: 535) TTR-463 Target:5′-GCACTTGGCATCTCCCCATTCCATGAG-3′ (SEQ ID NO: 919)5′-CACUUGGCAUCUCCCCAUUCCAUGAGC-3′ (SEQ ID NO: 2072)3′-GUGAACCGUAGAGGGGUAAGGUACUCG-5′ (SEQ ID NO: 536) TTR-464 Target:5′-CACTTGGCATCTCCCCATTCCATGAGC-3′ (SEQ ID NO: 920)5′-ACUUGGCAUCUCCCCAUUCCAUGAGCA-3′ (SEQ ID NO: 2073)3′-UGAACCGUAGAGGGGUAAGGUACUCGU-5′ (SEQ ID NO: 537) TTR-465 Target:5′-ACTTGGCATCTCCCCATTCCATGAGCA-3′ (SEQ ID NO: 921)5′-CUUGGCAUCUCCCCAUUCCAUGAGCAU-3′ (SEQ ID NO: 2074)3′-GAACCGUAGAGGGGUAAGGUACUCGUA-5′ (SEQ ID NO: 538) TTR-466 Target:5′-CTTGGCATCTCCCCATTCCATGAGCAT-3′ (SEQ ID NO: 922)5′-UUGGCAUCUCCCCAUUCCAUGAGCAUG-3′ (SEQ ID NO: 2075)3′-AACCGUAGAGGGGUAAGGUACUCGUAC-5′ (SEQ ID NO: 539) TTR-467 Target:5′-TTGGCATCTCCCCATTCCATGAGCATG-3′ (SEQ ID NO: 923)5′-UGGCAUCUCCCCAUUCCAUGAGCAUGC-3′ (SEQ ID NO: 2076)3′-ACCGUAGAGGGGUAAGGUACUCGUACG-5′ (SEQ ID NO: 540) TTR-468 Target:5′-TGGCATCTCCCCATTCCATGAGCATGC-3′ (SEQ ID NO: 924)5′-GGCAUCUCCCCAUUCCAUGAGCAUGCA-3′ (SEQ ID NO: 2077)3′-CCGUAGAGGGGUAAGGUACUCGUACGU-5′ (SEQ ID NO: 541) TTR-469 Target:5′-GGCATCTCCCCATTCCATGAGCATGCA-3′ (SEQ ID NO: 925)5′-GCAUCUCCCCAUUCCAUGAGCAUGCAG-3′ (SEQ ID NO: 2078)3′-CGUAGAGGGGUAAGGUACUCGUACGUC-5′ (SEQ ID NO: 542) TTR-470 Target:5′-GCATCTCCCCATTCCATGAGCATGCAG-3′ (SEQ ID NO: 926)5′-CAUCUCCCCAUUCCAUGAGCAUGCAGA-3′ (SEQ ID NO: 2079)3′-GUAGAGGGGUAAGGUACUCGUACGUCU-5′ (SEQ ID NO: 543) TTR-471 Target:5′-CATCTCCCCATTCCATGAGCATGCAGA-3′ (SEQ ID NO: 927)5′-AUCUCCCCAUUCCAUGAGCAUGCAGAG-3′ (SEQ ID NO: 2080)3′-UAGAGGGGUAAGGUACUCGUACGUCUC-5′ (SEQ ID NO: 544) TTR-472 Target:5′-ATCTCCCCATTCCATGAGCATGCAGAG-3′ (SEQ ID NO: 928)5′-UCUCCCCAUUCCAUGAGCAUGCAGAGG-3′ (SEQ ID NO: 2081)3′-AGAGGGGUAAGGUACUCGUACGUCUCC-5′ (SEQ ID NO: 545) TTR-473 Target:5′-TCTCCCCATTCCATGAGCATGCAGAGG-3′ (SEQ ID NO: 929)5′-CUCCCCAUUCCAUGAGCAUGCAGAGGU-3′ (SEQ ID NO: 2082)3′-GAGGGGUAAGGUACUCGUACGUCUCCA-5′ (SEQ ID NO: 546) TTR-474 Target:5′-CTCCCCATTCCATGAGCATGCAGAGGT-3′ (SEQ ID NO: 930)5′-UCCAUGAGCAUGCAGAGGUGGUAUUCA-3′ (SEQ ID NO: 2083)3′-AGGUACUCGUACGUCUCCACCAUAAGU-5′ (SEQ ID NO: 547) TTR-482 Target:5′-TCCATGAGCATGCAGAGGTGGTATTCA-3′ (SEQ ID NO: 931)5′-CCAUGAGCAUGCAGAGGUGGUAUUCAC-3′ (SEQ ID NO: 2084)3′-GGUACUCGUACGUCUCCACCAUAAGUG-5′ (SEQ ID NO: 548) TTR-483 Target:5′-CCATGAGCATGCAGAGGTGGTATTCAC-3′ (SEQ ID NO: 932)5′-CAUGAGCAUGCAGAGGUGGUAUUCACA-3′ (SEQ ID NO: 2085)3′-GUACUCGUACGUCUCCACCAUAAGUGU-5′ (SEQ ID NO: 549) TTR-484 Target:5′-CATGAGCATGCAGAGGTGGTATTCACA-3′ (SEQ ID NO: 933)5′-AUGAGCAUGCAGAGGUGGUAUUCACAG-3′ (SEQ ID NO: 2086)3′-UACUCGUACGUCUCCACCAUAAGUGUC-5′ (SEQ ID NO: 550) TTR-485 Target:5′-ATGAGCATGCAGAGGTGGTATTCACAG-3′ (SEQ ID NO: 934)5′-GCAUGCAGAGGUGGUAUUCACAGCCAA-3′ (SEQ ID NO: 2087)3′-CGUACGUCUCCACCAUAAGUGUCGGUU-5′ (SEQ ID NO: 551) TTR-489 Target:5′-GCATGCAGAGGTGGTATTCACAGCCAA-3′ (SEQ ID NO: 935)5′-GCAGAGGUGGUAUUCACAGCCAACGAC-3′ (SEQ ID NO: 2088)3′-CGUCUCCACCAUAAGUGUCGGUUGCUG-5′ (SEQ ID NO: 552) TTR-493 Target:5′-GCAGAGGTGGTATTCACAGCCAACGAC-3′ (SEQ ID NO: 936)5′-CAGAGGUGGUAUUCACAGCCAACGACU-3′ (SEQ ID NO: 2089)3′-GUCUCCACCAUAAGUGUCGGUUGCUGA-5′ (SEQ ID NO: 553) TTR-494 Target:5′-CAGAGGTGGTATTCACAGCCAACGACT-3′ (SEQ ID NO: 937)5′-CUGUCGUCACCAAUCCCAAGGAAUGAG-3′ (SEQ ID NO: 2090)3′-GACAGCAGUGGUUAGGGUUCCUUACUC-5′ (SEQ ID NO: 554) TTR-581 Target:5′-CTGTCGTCACCAATCCCAAGGAATGAG-3′ (SEQ ID NO: 938)5′-AAGGACGAGGGAUGGGAUUUCAUGUAA-3′ (SEQ ID NO: 2091)3′-UUCCUGCUCCCUACCCUAAAGUACAUU-5′ (SEQ ID NO: 555) TTR-631 Target:5′-AAGGACGAGGGATGGGATTTCATGTAA-3′ (SEQ ID NO: 939)5′-AGGACGAGGGAUGGGAUUUCAUGUAAC-3′ (SEQ ID NO: 2092)3′-UCCUGCUCCCUACCCUAAAGUACAUUG-5′ (SEQ ID NO: 556) TTR-632 Target:5′-AGGACGAGGGATGGGATTTCATGTAAC-3′ (SEQ ID NO: 940)5′-ACGAGGGAUGGGAUUUCAUGUAACCAA-3′ (SEQ ID NO: 2093)3′-UGCUCCCUACCCUAAAGUACAUUGGUU-5′ (SEQ ID NO: 557) TTR-635 Target:5′-ACGAGGGATGGGATTTCATGTAACCAA-3′ (SEQ ID NO: 941)5′-CGAGGGAUGGGAUUUCAUGUAACCAAG-3′ (SEQ ID NO: 2094)3′-GCUCCCUACCCUAAAGUACAUUGGUUC-5′ (SEQ ID NO: 558) TTR-636 Target:5′-CGAGGGATGGGATTTCATGTAACCAAG-3′ (SEQ ID NO: 942)5′-GAGGGAUGGGAUUUCAUGUAACCAAGA-3′ (SEQ ID NO: 2095)3′-CUCCCUACCCUAAAGUACAUUGGUUCU-5′ (SEQ ID NO: 559) TTR-637 Target:5′-GAGGGATGGGATTTCATGTAACCAAGA-3′ (SEQ ID NO: 943)5′-GGGAUGGGAUUUCAUGUAACCAAGAGU-3′ (SEQ ID NO: 2096)3′-CCCUACCCUAAAGUACAUUGGUUCUCA-5′ (SEQ ID NO: 560) TTR-639 Target:5′-GGGATGGGATTTCATGTAACCAAGAGT-3′ (SEQ ID NO: 944)5′-GGAUGGGAUUUCAUGUAACCAAGAGUA-3′ (SEQ ID NO: 2097)3′-CCUACCCUAAAGUACAUUGGUUCUCAU-5′ (SEQ ID NO: 561) TTR-640 Target:5′-GGATGGGATTTCATGTAACCAAGAGTA-3′ (SEQ ID NO: 945)5′-GAUGGGAUUUCAUGUAACCAAGAGUAU-3′ (SEQ ID NO: 2098)3′-CUACCCUAAAGUACAUUGGUUCUCAUA-5′ (SEQ ID NO: 562) TTR-641 Target:5′-GATGGGATTTCATGTAACCAAGAGTAT-3′ (SEQ ID NO: 946)5′-AUGGGAUUUCAUGUAACCAAGAGUAUU-3′ (SEQ ID NO: 2099)3′-UACCCUAAAGUACAUUGGUUCUCAUAA-5′ (SEQ ID NO: 563) TTR-642 Target:5′-ATGGGATTTCATGTAACCAAGAGTATT-3′ (SEQ ID NO: 947)5′-UGGGAUUUCAUGUAACCAAGAGUAUUC-3′ (SEQ ID NO: 2100)3′-ACCCUAAAGUACAUUGGUUCUCAUAAG-5′ (SEQ ID NO: 564) TTR-643 Target:5′-TGGGATTTCATGTAACCAAGAGTATTC-3′ (SEQ ID NO: 948)5′-GGGAUUUCAUGUAACCAAGAGUAUUCC-3′ (SEQ ID NO: 2101)3′-CCCUAAAGUACAUUGGUUCUCAUAAGG-5′ (SEQ ID NO: 565) TTR-644 Target:5′-GGGATTTCATGTAACCAAGAGTATTCC-3′ (SEQ ID NO: 949)5′-GGAUUUCAUGUAACCAAGAGUAUUCCA-3′ (SEQ ID NO: 2102)3′-CCUAAAGUACAUUGGUUCUCAUAAGGU-5′ (SEQ ID NO: 566) TTR-645 Target:5′-GGATTTCATGTAACCAAGAGTATTCCA-3′ (SEQ ID NO: 950)5′-GAUUUCAUGUAACCAAGAGUAUUCCAU-3′ (SEQ ID NO: 2103)3′-CUAAAGUACAUUGGUUCUCAUAAGGUA-5′ (SEQ ID NO: 567) TTR-646 Target:5′-GATTTCATGTAACCAAGAGTATTCCAT-3′ (SEQ ID NO: 951)5′-AUUUCAUGUAACCAAGAGUAUUCCAUU-3′ (SEQ ID NO: 2104)3′-UAAAGUACAUUGGUUCUCAUAAGGUAA-5′ (SEQ ID NO: 568) TTR-647 Target:5′-ATTTCATGTAACCAAGAGTATTCCATT-3′ (SEQ ID NO: 952)5′-UUUCAUGUAACCAAGAGUAUUCCAUUU-3′ (SEQ ID NO: 2105)3′-AAAGUACAUUGGUUCUCAUAAGGUAAA-5′ (SEQ ID NO: 569) TTR-648 Target:5′-TTTCATGTAACCAAGAGTATTCCATTT-3′ (SEQ ID NO: 953)5′-UUCAUGUAACCAAGAGUAUUCCAUUUU-3′ (SEQ ID NO: 2106)3′-AAGUACAUUGGUUCUCAUAAGGUAAAA-5′ (SEQ ID NO: 570) TTR-649 Target:5′-TTCATGTAACCAAGAGTATTCCATTTT-3′ (SEQ ID NO: 954)5′-UCAUGUAACCAAGAGUAUUCCAUUUUU-3′ (SEQ ID NO: 2107)3′-AGUACAUUGGUUCUCAUAAGGUAAAAA-5′ (SEQ ID NO: 571) TTR-650 Target:5′-TCATGTAACCAAGAGTATTCCATTTTT-3′ (SEQ ID NO: 955)5′-CAUGUAACCAAGAGUAUUCCAUUUUUA-3′ (SEQ ID NO: 2108)3′-GUACAUUGGUUCUCAUAAGGUAAAAAU-5′ (SEQ ID NO: 572) TTR-651 Target:5′-CATGTAACCAAGAGTATTCCATTTTTA-3′ (SEQ ID NO: 956)5′-AUGUAACCAAGAGUAUUCCAUUUUUAC-3′ (SEQ ID NO: 2109)3′-UACAUUGGUUCUCAUAAGGUAAAAAUG-5′ (SEQ ID NO: 573) TTR-652 Target:5′-ATGTAACCAAGAGTATTCCATTTTTAC-3′ (SEQ ID NO: 957)5′-UGUAACCAAGAGUAUUCCAUUUUUACU-3′ (SEQ ID NO: 2110)3′-ACAUUGGUUCUCAUAAGGUAAAAAUGA-5′ (SEQ ID NO: 574) TTR-653 Target:5′-TGTAACCAAGAGTATTCCATTTTTACT-3′ (SEQ ID NO: 958)5′-GUAACCAAGAGUAUUCCAUUUUUACUA-3′ (SEQ ID NO: 2111)3′-CAUUGGUUCUCAUAAGGUAAAAAUGAU-5′ (SEQ ID NO: 575) TTR-654 Target:5′-GTAACCAAGAGTATTCCATTTTTACTA-3′ (SEQ ID NO: 959)5′-UAACCAAGAGUAUUCCAUUUUUACUAA-3′ (SEQ ID NO: 2112)3′-AUUGGUUCUCAUAAGGUAAAAAUGAUU-5′ (SEQ ID NO: 576) TTR-655 Target:5′-TAACCAAGAGTATTCCATTTTTACTAA-3′ (SEQ ID NO: 960)5′-AACCAAGAGUAUUCCAUUUUUACUAAA-3′ (SEQ ID NO: 2113)3′-UUGGUUCUCAUAAGGUAAAAAUGAUUU-5′ (SEQ ID NO: 577) TTR-656 Target:5′-AACCAAGAGTATTCCATTTTTACTAAA-3′ (SEQ ID NO: 961)5′-ACCAAGAGUAUUCCAUUUUUACUAAAG-3′ (SEQ ID NO: 2114)3′-UGGUUCUCAUAAGGUAAAAAUGAUUUC-5′ (SEQ ID NO: 578) TTR-657 Target:5′-ACCAAGAGTATTCCATTTTTACTAAAG-3′ (SEQ ID NO: 962)5′-CCAAGAGUAUUCCAUUUUUACUAAAGC-3′ (SEQ ID NO: 2115)3′-GGUUCUCAUAAGGUAAAAAUGAUUUCG-5′ (SEQ ID NO: 579) TTR-658 Target:5′-CCAAGAGTATTCCATTTTTACTAAAGC-3′ (SEQ ID NO: 963)5′-CAAGAGUAUUCCAUUUUUACUAAAGCA-3′ (SEQ ID NO: 2116)3′-GUUCUCAUAAGGUAAAAAUGAUUUCGU-5′ (SEQ ID NO: 580) TTR-659 Target:5′-CAAGAGTATTCCATTTTTACTAAAGCA-3′ (SEQ ID NO: 964)5′-AAGAGUAUUCCAUUUUUACUAAAGCAG-3′ (SEQ ID NO: 2117)3′-UUCUCAUAAGGUAAAAAUGAUUUCGUC-5′ (SEQ ID NO: 581) TTR-660 Target:5′-AAGAGTATTCCATTTTTACTAAAGCAG-3′ (SEQ ID NO: 965)5′-AGAGUAUUCCAUUUUUACUAAAGCAGU-3′ (SEQ ID NO: 2118)3′-UCUCAUAAGGUAAAAAUGAUUUCGUCA-5′ (SEQ ID NO: 582) TTR-661 Target:5′-AGAGTATTCCATTTTTACTAAAGCAGT-3′ (SEQ ID NO: 966)5′-GAGUAUUCCAUUUUUACUAAAGCAGUG-3′ (SEQ ID NO: 2119)3′-CUCAUAAGGUAAAAAUGAUUUCGUCAC-5′ (SEQ ID NO: 583) TTR-662 Target:5′-GAGTATTCCATTTTTACTAAAGCAGTG-3′ (SEQ ID NO: 967)5′-AGUAUUCCAUUUUUACUAAAGCAGUGU-3′ (SEQ ID NO: 2120)3′-UCAUAAGGUAAAAAUGAUUUCGUCACA-5′ (SEQ ID NO: 584) TTR-663 Target:5′-AGTATTCCATTTTTACTAAAGCAGTGT-3′ (SEQ ID NO: 968)5′-GUAUUCCAUUUUUACUAAAGCAGUGUU-3′ (SEQ ID NO: 2121)3′-CAUAAGGUAAAAAUGAUUUCGUCACAA-5′ (SEQ ID NO: 585) TTR-664 Target:5′-GTATTCCATTTTTACTAAAGCAGTGTT-3′ (SEQ ID NO: 969)5′-UAUUCCAUUUUUACUAAAGCAGUGUUU-3′ (SEQ ID NO: 2122)3′-AUAAGGUAAAAAUGAUUUCGUCACAAA-5′ (SEQ ID NO: 586) TTR-665 Target:5′-TATTCCATTTTTACTAAAGCAGTGTTT-3′ (SEQ ID NO: 970)5′-AUUCCAUUUUUACUAAAGCAGUGUUUU-3′ (SEQ ID NO: 2123)3′-UAAGGUAAAAAUGAUUUCGUCACAAAA-5′ (SEQ ID NO: 587) TTR-666 Target:5′-ATTCCATTTTTACTAAAGCAGTGTTTT-3′ (SEQ ID NO: 971)5′-UUCCAUUUUUACUAAAGCAGUGUUUUC-3′ (SEQ ID NO: 2124)3′-AAGGUAAAAAUGAUUUCGUCACAAAAG-5′ (SEQ ID NO: 588) TTR-667 Target:5′-TTCCATTTTTACTAAAGCAGTGTTTTC-3′ (SEQ ID NO: 972)5′-UCCAUUUUUACUAAAGCAGUGUUUUCA-3′ (SEQ ID NO: 2125)3′-AGGUAAAAAUGAUUUCGUCACAAAAGU-5′ (SEQ ID NO: 589) TTR-668 Target:5′-TCCATTTTTACTAAAGCAGTGTTTTCA-3′ (SEQ ID NO: 973)5′-CCAUUUUUACUAAAGCAGUGUUUUCAC-3′ (SEQ ID NO: 2126)3′-GGUAAAAAUGAUUUCGUCACAAAAGUG-5′ (SEQ ID NO: 590) TTR-669 Target:5′-CCATTTTTACTAAAGCAGTGTTTTCAC-3′ (SEQ ID NO: 974)5′-CAUUUUUACUAAAGCAGUGUUUUCACC-3′ (SEQ ID NO: 2127)3′-GUAAAAAUGAUUUCGUCACAAAAGUGG-5′ (SEQ ID NO: 591) TTR-670 Target:5′-CATTTTTACTAAAGCAGTGTTTTCACC-3′ (SEQ ID NO: 975)5′-AUUUUUACUAAAGCAGUGUUUUCACCU-3′ (SEQ ID NO: 2128)3′-UAAAAAUGAUUUCGUCACAAAAGUGGA-5′ (SEQ ID NO: 592) TTR-671 Target:5′-ATTTTTACTAAAGCAGTGTTTTCACCT-3′ (SEQ ID NO: 976)5′-UUUUUACUAAAGCAGUGUUUUCACCUC-3′ (SEQ ID NO: 2129)3′-AAAAAUGAUUUCGUCACAAAAGUGGAG-5′ (SEQ ID NO: 593) TTR-672 Target:5′-TTTTTACTAAAGCAGTGTTTTCACCTC-3′ (SEQ ID NO: 977)5′-UUUUACUAAAGCAGUGUUUUCACCUCA-3′ (SEQ ID NO: 2130)3′-AAAAUGAUUUCGUCACAAAAGUGGAGU-5′ (SEQ ID NO: 594) TTR-673 Target:5′-TTTTACTAAAGCAGTGTTTTCACCTCA-3′ (SEQ ID NO: 978)5′-UUUACUAAAGCAGUGUUUUCACCUCAU-3′ (SEQ ID NO: 2131)3′-AAAUGAUUUCGUCACAAAAGUGGAGUA-5′ (SEQ ID NO: 595) TTR-674 Target:5′-TTTACTAAAGCAGTGTTTTCACCTCAT-3′ (SEQ ID NO: 979)5′-UUACUAAAGCAGUGUUUUCACCUCAUA-3′ (SEQ ID NO: 2132)3′-AAUGAUUUCGUCACAAAAGUGGAGUAU-5′ (SEQ ID NO: 596) TTR-675 Target:5′-TTACTAAAGCAGTGTTTTCACCTCATA-3′ (SEQ ID NO: 980)5′-UACUAAAGCAGUGUUUUCACCUCAUAU-3′ (SEQ ID NO: 2133)3′-AUGAUUUCGUCACAAAAGUGGAGUAUA-5′ (SEQ ID NO: 597) TTR-676 Target:5′-TACTAAAGCAGTGTTTTCACCTCATAT-3′ (SEQ ID NO: 981)5′-ACUAAAGCAGUGUUUUCACCUCAUAUG-3′ (SEQ ID NO: 2134)3′-UGAUUUCGUCACAAAAGUGGAGUAUAC-5′ (SEQ ID NO: 598) TTR-677 Target:5′-ACTAAAGCAGTGTTTTCACCTCATATG-3′ (SEQ ID NO: 982)5′-CUAAAGCAGUGUUUUCACCUCAUAUGC-3′ (SEQ ID NO: 2135)3′-GAUUUCGUCACAAAAGUGGAGUAUACG-5′ (SEQ ID NO: 599) TTR-678 Target:5′-CTAAAGCAGTGTTTTCACCTCATATGC-3′ (SEQ ID NO: 983)5′-UAAAGCAGUGUUUUCACCUCAUAUGCU-3′ (SEQ ID NO: 2136)3′-AUUUCGUCACAAAAGUGGAGUAUACGA-5′ (SEQ ID NO: 600) TTR-679 Target:5′-TAAAGCAGTGTTTTCACCTCATATGCT-3′ (SEQ ID NO: 984)5′-AAAGCAGUGUUUUCACCUCAUAUGCUA-3′ (SEQ ID NO: 2137)3′-UUUCGUCACAAAAGUGGAGUAUACGAU-5′ (SEQ ID NO: 601) TTR-680 Target:5′-AAAGCAGTGTTTTCACCTCATATGCTA-3′ (SEQ ID NO: 985)5′-AAGCAGUGUUUUCACCUCAUAUGCUAU-3′ (SEQ ID NO: 2138)3′-UUCGUCACAAAAGUGGAGUAUACGAUA-5′ (SEQ ID NO: 602) TTR-681 Target:5′-AAGCAGTGTTTTCACCTCATATGCTAT-3′ (SEQ ID NO: 986)5′-AGCAGUGUUUUCACCUCAUAUGCUAUG-3′ (SEQ ID NO: 2139)3′-UCGUCACAAAAGUGGAGUAUACGAUAC-5′ (SEQ ID NO: 603) TTR-682 Target:5′-AGCAGTGTTTTCACCTCATATGCTATG-3′ (SEQ ID NO: 987)5′-GCAGUGUUUUCACCUCAUAUGCUAUGU-3′ (SEQ ID NO: 2140)3′-CGUCACAAAAGUGGAGUAUACGAUACA-5′ (SEQ ID NO: 604) TTR-683 Target:5′-GCAGTGTTTTCACCTCATATGCTATGT-3′ (SEQ ID NO: 988)5′-CAGUGUUUUCACCUCAUAUGCUAUGUU-3′ (SEQ ID NO: 2141)3′-GUCACAAAAGUGGAGUAUACGAUACAA-5′ (SEQ ID NO: 605) TTR-684 Target:5′-CAGTGTTTTCACCTCATATGCTATGTT-3′ (SEQ ID NO: 989)5′-AGUGUUUUCACCUCAUAUGCUAUGUUA-3′ (SEQ ID NO: 2142)3′-UCACAAAAGUGGAGUAUACGAUACAAU-5′ (SEQ ID NO: 606) TTR-685 Target:5′-AGTGTTTTCACCTCATATGCTATGTTA-3′ (SEQ ID NO: 990)5′-GUGUUUUCACCUCAUAUGCUAUGUUAG-3′ (SEQ ID NO: 2143)3′-CACAAAAGUGGAGUAUACGAUACAAUC-5′ (SEQ ID NO: 607) TTR-686 Target:5′-GTGTTTTCACCTCATATGCTATGTTAG-3′ (SEQ ID NO: 991)5′-UGUUUUCACCUCAUAUGCUAUGUUAGA-3′ (SEQ ID NO: 2144)3′-ACAAAAGUGGAGUAUACGAUACAAUCU-5′ (SEQ ID NO: 608) TTR-687 Target:5′-TGTTTTCACCTCATATGCTATGTTAGA-3′ (SEQ ID NO: 992)5′-GUUUUCACCUCAUAUGCUAUGUUAGAA-3′ (SEQ ID NO: 2145)3′-CAAAAGUGGAGUAUACGAUACAAUCUU-5′ (SEQ ID NO: 609) TTR-688 Target:5′-GTTTTCACCTCATATGCTATGTTAGAA-3′ (SEQ ID NO: 993)5′-UUUUCACCUCAUAUGCUAUGUUAGAAG-3′ (SEQ ID NO: 2146)3′-AAAAGUGGAGUAUACGAUACAAUCUUC-5′ (SEQ ID NO: 610) TTR-689 Target:5′-TTTTCACCTCATATGCTATGTTAGAAG-3′ (SEQ ID NO: 994)5′-UUUCACCUCAUAUGCUAUGUUAGAAGU-3′ (SEQ ID NO: 2147)3′-AAAGUGGAGUAUACGAUACAAUCUUCA-5′ (SEQ ID NO: 611) TTR-690 Target:5′-TTTCACCTCATATGCTATGTTAGAAGT-3′ (SEQ ID NO: 995)5′-UUCACCUCAUAUGCUAUGUUAGAAGUC-3′ (SEQ ID NO: 2148)3′-AAGUGGAGUAUACGAUACAAUCUUCAG-5′ (SEQ ID NO: 612) TTR-691 Target:5′-TTCACCTCATATGCTATGTTAGAAGTC-3′ (SEQ ID NO: 996)5′-UCACCUCAUAUGCUAUGUUAGAAGUCC-3′ (SEQ ID NO: 2149)3′-AGUGGAGUAUACGAUACAAUCUUCAGG-5′ (SEQ ID NO: 613) TTR-692 Target:5′-TCACCTCATATGCTATGTTAGAAGTCC-3′ (SEQ ID NO: 997)5′-CACCUCAUAUGCUAUGUUAGAAGUCCA-3′ (SEQ ID NO: 2150)3′-GUGGAGUAUACGAUACAAUCUUCAGGU-5′ (SEQ ID NO: 614) TTR-693 Target:5′-CACCTCATATGCTATGTTAGAAGTCCA-3′ (SEQ ID NO: 998)5′-ACCUCAUAUGCUAUGUUAGAAGUCCAG-3′ (SEQ ID NO: 2151)3′-UGGAGUAUACGAUACAAUCUUCAGGUC-5′ (SEQ ID NO: 615) TTR-694 Target:5′-ACCTCATATGCTATGTTAGAAGTCCAG-3′ (SEQ ID NO: 999)5′-CCUCAUAUGCUAUGUUAGAAGUCCAGG-3′ (SEQ ID NO: 2152)3′-GGAGUAUACGAUACAAUCUUCAGGUCC-5′ (SEQ ID NO: 616) TTR-695 Target:5′-CCTCATATGCTATGTTAGAAGTCCAGG-3′ (SEQ ID NO: 1000)5′-CUCAUAUGCUAUGUUAGAAGUCCAGGC-3′ (SEQ ID NO: 2153)3′-GAGUAUACGAUACAAUCUUCAGGUCCG-5′ (SEQ ID NO: 617) TTR-696 Target:5′-CTCATATGCTATGTTAGAAGTCCAGGC-3′ (SEQ ID NO: 1001)5′-UCAUAUGCUAUGUUAGAAGUCCAGGCA-3′ (SEQ ID NO: 2154)3′-AGUAUACGAUACAAUCUUCAGGUCCGU-5′ (SEQ ID NO: 618) TTR-697 Target:5′-TCATATGCTATGTTAGAAGTCCAGGCA-3′ (SEQ ID NO: 1002)5′-CAUAUGCUAUGUUAGAAGUCCAGGCAG-3′ (SEQ ID NO: 2155)3′-GUAUACGAUACAAUCUUCAGGUCCGUC-5′ (SEQ ID NO: 619) TTR-698 Target:5′-CATATGCTATGTTAGAAGTCCAGGCAG-3′ (SEQ ID NO: 1003)5′-AUAUGCUAUGUUAGAAGUCCAGGCAGA-3′ (SEQ ID NO: 2156)3′-UAUACGAUACAAUCUUCAGGUCCGUCU-5′ (SEQ ID NO: 620) TTR-699 Target:5′-ATATGCTATGTTAGAAGTCCAGGCAGA-3′ (SEQ ID NO: 1004)5′-UGCUAUGUUAGAAGUCCAGGCAGAGAC-3′ (SEQ ID NO: 2157)3′-ACGAUACAAUCUUCAGGUCCGUCUCUG-5′ (SEQ ID NO: 621) TTR-702 Target:5′-TGCTATGTTAGAAGTCCAGGCAGAGAC-3′ (SEQ ID NO: 1005)5′-CUAUGUUAGAAGUCCAGGCAGAGACAA-3′ (SEQ ID NO: 2158)3′-GAUACAAUCUUCAGGUCCGUCUCUGUU-5′ (SEQ ID NO: 622) TTR-704 Target:5′-CTATGTTAGAAGTCCAGGCAGAGACAA-3′ (SEQ ID NO: 1006)5′-UAUGUUAGAAGUCCAGGCAGAGACAAU-3′ (SEQ ID NO: 2159)3′-AUACAAUCUUCAGGUCCGUCUCUGUUA-5′ (SEQ ID NO: 623) TTR-705 Target:5′-TATGTTAGAAGTCCAGGCAGAGACAAT-3′ (SEQ ID NO: 1007)5′-AUGUUAGAAGUCCAGGCAGAGACAAUA-3′ (SEQ ID NO: 2160)3′-UACAAUCUUCAGGUCCGUCUCUGUUAU-5′ (SEQ ID NO: 624) TTR-706 Target:5′-ATGTTAGAAGTCCAGGCAGAGACAATA-3′ (SEQ ID NO: 1008)5′-UGUUAGAAGUCCAGGCAGAGACAAUAA-3′ (SEQ ID NO: 2161)3′-ACAAUCUUCAGGUCCGUCUCUGUUAUU-5′ (SEQ ID NO: 625) TTR-707 Target:5′-TGTTAGAAGTCCAGGCAGAGACAATAA-3′ (SEQ ID NO: 1009)5′-GUUAGAAGUCCAGGCAGAGACAAUAAA-3′ (SEQ ID NO: 2162)3′-CAAUCUUCAGGUCCGUCUCUGUUAUUU-5′ (SEQ ID NO: 626) TTR-708 Target:5′-GTTAGAAGTCCAGGCAGAGACAATAAA-3′ (SEQ ID NO: 1010)5′-UUAGAAGUCCAGGCAGAGACAAUAAAA-3′ (SEQ ID NO: 2163)3′-AAUCUUCAGGUCCGUCUCUGUUAUUUU-5′ (SEQ ID NO: 627) TTR-709 Target:5′-TTAGAAGTCCAGGCAGAGACAATAAAA-3′ (SEQ ID NO: 1011)5′-UAGAAGUCCAGGCAGAGACAAUAAAAC-3′ (SEQ ID NO: 2164)3′-AUCUUCAGGUCCGUCUCUGUUAUUUUG-5′ (SEQ ID NO: 628) TTR-710 Target:5′-TAGAAGTCCAGGCAGAGACAATAAAAC-3′ (SEQ ID NO: 1012)5′-AGAAGUCCAGGCAGAGACAAUAAAACA-3′ (SEQ ID NO: 2165)3′-UCUUCAGGUCCGUCUCUGUUAUUUUGU-5′ (SEQ ID NO: 629) TTR-711 Target:5′-AGAAGTCCAGGCAGAGACAATAAAACA-3′ (SEQ ID NO: 1013)5′-GAAGUCCAGGCAGAGACAAUAAAACAU-3′ (SEQ ID NO: 2166)3′-CUUCAGGUCCGUCUCUGUUAUUUUGUA-5′ (SEQ ID NO: 630) TTR-712 Target:5′-GAAGTCCAGGCAGAGACAATAAAACAT-3′ (SEQ ID NO: 1014)5′-AAGUCCAGGCAGAGACAAUAAAACAUU-3′ (SEQ ID NO: 2167)3′-UUCAGGUCCGUCUCUGUUAUUUUGUAA-5′ (SEQ ID NO: 631) TTR-713 Target:5′-AAGTCCAGGCAGAGACAATAAAACATT-3′ (SEQ ID NO: 1015)5′-AGUCCAGGCAGAGACAAUAAAACAUUC-3′ (SEQ ID NO: 2168)3′-UCAGGUCCGUCUCUGUUAUUUUGUAAG-5′ (SEQ ID NO: 632) TTR-714 Target:5′-AGTCCAGGCAGAGACAATAAAACATTC-3′ (SEQ ID NO: 1016)5′-UCCAGGCAGAGACAAUAAAACAUUCCU-3′ (SEQ ID NO: 2169)3′-AGGUCCGUCUCUGUUAUUUUGUAAGGA-5′ (SEQ ID NO: 633) TTR-716 Target:5′-TCCAGGCAGAGACAATAAAACATTCCT-3′ (SEQ ID NO: 1017)5′-CCAGGCAGAGACAAUAAAACAUUCCUG-3′ (SEQ ID NO: 2170)3′-GGUCCGUCUCUGUUAUUUUGUAAGGAC-5′ (SEQ ID NO: 634) TTR-717 Target:5′-CCAGGCAGAGACAATAAAACATTCCTG-3′ (SEQ ID NO: 1018)5′-CAGGCAGAGACAAUAAAACAUUCCUGU-3′ (SEQ ID NO: 2171)3′-GUCCGUCUCUGUUAUUUUGUAAGGACA-5′ (SEQ ID NO: 635) TTR-718 Target:5′-CAGGCAGAGACAATAAAACATTCCTGT-3′ (SEQ ID NO: 1019)5′-AGGCAGAGACAAUAAAACAUUCCUGUG-3′ (SEQ ID NO: 2172)3′-UCCGUCUCUGUUAUUUUGUAAGGACAC-5′ (SEQ ID NO: 636) TTR-719 Target:5′-AGGCAGAGACAATAAAACATTCCTGTG-3′ (SEQ ID NO: 1020)5′-GGCAGAGACAAUAAAACAUUCCUGUGA-3′ (SEQ ID NO: 2173)3′-CCGUCUCUGUUAUUUUGUAAGGACACU-5′ (SEQ ID NO: 637) TTR-720 Target:5′-GGCAGAGACAATAAAACATTCCTGTGA-3′ (SEQ ID NO: 1021)5′-GCAGAGACAAUAAAACAUUCCUGUGAA-3′ (SEQ ID NO: 2174)3′-CGUCUCUGUUAUUUUGUAAGGACACUU-5′ (SEQ ID NO: 638) TTR-721 Target:5′-GCAGAGACAATAAAACATTCCTGTGAA-3′ (SEQ ID NO: 1022)5′-CAGAGACAAUAAAACAUUCCUGUGAAA-3′ (SEQ ID NO: 2175)3′-GUCUCUGUUAUUUUGUAAGGACACUUU-5′ (SEQ ID NO: 639) TTR-722 Target:5′-CAGAGACAATAAAACATTCCTGTGAAA-3′ (SEQ ID NO: 1023)5′-AGAGACAAUAAAACAUUCCUGUGAAAG-3′ (SEQ ID NO: 2176)3′-UCUCUGUUAUUUUGUAAGGACACUUUC-5′ (SEQ ID NO: 640) TTR-723 Target:5′-AGAGACAATAAAACATTCCTGTGAAAG-3′ (SEQ ID NO: 1024)5′-GAGACAAUAAAACAUUCCUGUGAAAGG-3′ (SEQ ID NO: 2177)3′-CUCUGUUAUUUUGUAAGGACACUUUCC-5′ (SEQ ID NO: 641) TTR-724 Target:5′-GAGACAATAAAACATTCCTGTGAAAGG-3′ (SEQ ID NO: 1025)5′-AGACAAUAAAACAUUCCUGUGAAAGGC-3′ (SEQ ID NO: 2178)3′-UCUGUUAUUUUGUAAGGACACUUUCCG-5′ (SEQ ID NO: 642) TTR-725 Target:5′-AGACAATAAAACATTCCTGTGAAAGGC-3′ (SEQ ID NO: 1026)5′-GACAAUAAAACAUUCCUGUGAAAGGCA-3′ (SEQ ID NO: 2179)3′-CUGUUAUUUUGUAAGGACACUUUCCGU-5′ (SEQ ID NO: 643) TTR-726 Target:5′-GACAATAAAACATTCCTGTGAAAGGCA-3′ (SEQ ID NO: 1027)5′-ACAAUAAAACAUUCCUGUGAAAGGCAC-3′ (SEQ ID NO: 2180)3′-UGUUAUUUUGUAAGGACACUUUCCGUG-5′ (SEQ ID NO: 644) TTR-727 Target:5′-ACAATAAAACATTCCTGTGAAAGGCAC-3′ (SEQ ID NO: 1028)5′-CAAUAAAACAUUCCUGUGAAAGGCACU-3′ (SEQ ID NO: 2181)3′-GUUAUUUUGUAAGGACACUUUCCGUGA-5′ (SEQ ID NO: 645) TTR-728 Target:5′-CAATAAAACATTCCTGTGAAAGGCACT-3′ (SEQ ID NO: 1029)5′-UAAAACAUUCCUGUGAAAGGCACUUUU-3′ (SEQ ID NO: 2182)3′-AUUUUGUAAGGACACUUUCCGUGAAAA-5′ (SEQ ID NO: 646) TTR-731 Target:5′-TAAAACATTCCTGTGAAAGGCACTTTT-3′ (SEQ ID NO: 1030)5′-AAAACAUUCCUGUGAAAGGCACUUUUC-3′ (SEQ ID NO: 2183)3′-UUUUGUAAGGACACUUUCCGUGAAAAG-5′ (SEQ ID NO: 647) TTR-732 Target:5′-AAAACATTCCTGTGAAAGGCACTTTTC-3′ (SEQ ID NO: 1031)5′-AAACAUUCCUGUGAAAGGCACUUUUCA-3′ (SEQ ID NO: 2184)3′-UUUGUAAGGACACUUUCCGUGAAAAGU-5′ (SEQ ID NO: 648) TTR-733 Target:5′-AAACATTCCTGTGAAAGGCACTTTTCA-3′ (SEQ ID NO: 1032)5′-AACAUUCCUGUGAAAGGCACUUUUCAU-3′ (SEQ ID NO: 2185)3′-UUGUAAGGACACUUUCCGUGAAAAGUA-5′ (SEQ ID NO: 649) TTR-734 Target:5′-AACATTCCTGTGAAAGGCACTTTTCAT-3′ (SEQ ID NO: 1033)5′-ACAUUCCUGUGAAAGGCACUUUUCAUU-3′ (SEQ ID NO: 2186)3′-UGUAAGGACACUUUCCGUGAAAAGUAA-5′ (SEQ ID NO: 650) TTR-735 Target:5′-ACATTCCTGTGAAAGGCACTTTTCATT-3′ (SEQ ID NO: 1034)5′-CAUUCCUGUGAAAGGCACUUUUCAUUC-3′ (SEQ ID NO: 2187)3′-GUAAGGACACUUUCCGUGAAAAGUAAG-5′ (SEQ ID NO: 651) TTR-736 Target:5′-CATTCCTGTGAAAGGCACTTTTCATTC-3′ (SEQ ID NO: 1035)5′-UUCCUGUGAAAGGCACUUUUCAUUCCA-3′ (SEQ ID NO: 2188)3′-AAGGACACUUUCCGUGAAAAGUAAGGU-5′ (SEQ ID NO: 652) TTR-738 Target:5′-TTCCTGTGAAAGGCACTTTTCATTCCA-3′ (SEQ ID NO: 1036)5′-UCCUGUGAAAGGCACUUUUCAUUCCAC-3′ (SEQ ID NO: 2189)3′-AGGACACUUUCCGUGAAAAGUAAGGUG-5′ (SEQ ID NO: 653) TTR-739 Target:5′-TCCTGTGAAAGGCACTTTTCATTCCAC-3′ (SEQ ID NO: 1037)5′-CCUGUGAAAGGCACUUUUCAUUCCACU-3′ (SEQ ID NO: 2190)3′-GGACACUUUCCGUGAAAAGUAAGGUGA-5′ (SEQ ID NO: 654) TTR-740 Target:5′-CCTGTGAAAGGCACTTTTCATTCCACT-3′ (SEQ ID NO: 1038)5′-CUGUGAAAGGCACUUUUCAUUCCACUU-3′ (SEQ ID NO: 2191)3′-GACACUUUCCGUGAAAAGUAAGGUGAA-5′ (SEQ ID NO: 655) TTR-741 Target:5′-CTGTGAAAGGCACTTTTCATTCCACTT-3′ (SEQ ID NO: 1039)5′-UGUGAAAGGCACUUUUCAUUCCACUUU-3′ (SEQ ID NO: 2192)3′-ACACUUUCCGUGAAAAGUAAGGUGAAA-5′ (SEQ ID NO: 656) TTR-742 Target:5′-TGTGAAAGGCACTTTTCATTCCACTTT-3′ (SEQ ID NO: 1040)5′-GUGAAAGGCACUUUUCAUUCCACUUUA-3′ (SEQ ID NO: 2193)3′-CACUUUCCGUGAAAAGUAAGGUGAAAU-5′ (SEQ ID NO: 657) TTR-743 Target:5′-GTGAAAGGCACTTTTCATTCCACTTTA-3′ (SEQ ID NO: 1041)5′-UGAAAGGCACUUUUCAUUCCACUUUAA-3′ (SEQ ID NO: 2194)3′-ACUUUCCGUGAAAAGUAAGGUGAAAUU-5′ (SEQ ID NO: 658) TTR-744 Target:5′-TGAAAGGCACTTTTCATTCCACTTTAA-3′ (SEQ ID NO: 1042)5′-GAAAGGCACUUUUCAUUCCACUUUAAC-3′ (SEQ ID NO: 2195)3′-CUUUCCGUGAAAAGUAAGGUGAAAUUG-5′ (SEQ ID NO: 659) TTR-745 Target:5′-GAAAGGCACTTTTCATTCCACTTTAAC-3′ (SEQ ID NO: 1043)5′-AAAGGCACUUUUCAUUCCACUUUAACU-3′ (SEQ ID NO: 2196)3′-UUUCCGUGAAAAGUAAGGUGAAAUUGA-5′ (SEQ ID NO: 660) TTR-746 Target:5′-AAAGGCACTTTTCATTCCACTTTAACT-3′ (SEQ ID NO: 1044)5′-AAGGCACUUUUCAUUCCACUUUAACUU-3′ (SEQ ID NO: 2197)3′-UUCCGUGAAAAGUAAGGUGAAAUUGAA-5′ (SEQ ID NO: 661) TTR-747 Target:5′-AAGGCACTTTTCATTCCACTTTAACTT-3′ (SEQ ID NO: 1045)5′-AGGCACUUUUCAUUCCACUUUAACUUG-3′ (SEQ ID NO: 2198)3′-UCCGUGAAAAGUAAGGUGAAAUUGAAC-5′ (SEQ ID NO: 662) TTR-748 Target:5′-AGGCACTTTTCATTCCACTTTAACTTG-3′ (SEQ ID NO: 1046)5′-GGCACUUUUCAUUCCACUUUAACUUGA-3′ (SEQ ID NO: 2199)3′-CCGUGAAAAGUAAGGUGAAAUUGAACU-5′ (SEQ ID NO: 663) TTR-749 Target:5′-GGCACTTTTCATTCCACTTTAACTTGA-3′ (SEQ ID NO: 1047)5′-GCACUUUUCAUUCCACUUUAACUUGAU-3′ (SEQ ID NO: 2200)3′-CGUGAAAAGUAAGGUGAAAUUGAACUA-5′ (SEQ ID NO: 664) TTR-750 Target:5′-GCACTTTTCATTCCACTTTAACTTGAT-3′ (SEQ ID NO: 1048)5′-CACUUUUCAUUCCACUUUAACUUGAUU-3′ (SEQ ID NO: 2201)3′-GUGAAAAGUAAGGUGAAAUUGAACUAA-5′ (SEQ ID NO: 665) TTR-751 Target:5′-CACTTTTCATTCCACTTTAACTTGATT-3′ (SEQ ID NO: 1049)5′-ACUUUUCAUUCCACUUUAACUUGAUUU-3′ (SEQ ID NO: 2202)3′-UGAAAAGUAAGGUGAAAUUGAACUAAA-5′ (SEQ ID NO: 666) TTR-752 Target:5′-ACTTTTCATTCCACTTTAACTTGATTT-3′ (SEQ ID NO: 1050)5′-CUUUUCAUUCCACUUUAACUUGAUUUU-3′ (SEQ ID NO: 2203)3′-GAAAAGUAAGGUGAAAUUGAACUAAAA-5′ (SEQ ID NO: 667) TTR-753 Target:5′-CTTTTCATTCCACTTTAACTTGATTTT-3′ (SEQ ID NO: 1051)5′-UUUUCAUUCCACUUUAACUUGAUUUUU-3′ (SEQ ID NO: 2204)3′-AAAAGUAAGGUGAAAUUGAACUAAAAA-5′ (SEQ ID NO: 668) TTR-754 Target:5′-TTTTCATTCCACTTTAACTTGATTTTT-3′ (SEQ ID NO: 1052)5′-UUUCAUUCCACUUUAACUUGAUUUUUU-3′ (SEQ ID NO: 2205)3′-AAAGUAAGGUGAAAUUGAACUAAAAAA-5′ (SEQ ID NO: 669) TTR-755 Target:5′-TTTCATTCCACTTTAACTTGATTTTTT-3′ (SEQ ID NO: 1053)5′-UUCAUUCCACUUUAACUUGAUUUUUUA-3′ (SEQ ID NO: 2206)3′-AAGUAAGGUGAAAUUGAACUAAAAAAU-5′ (SEQ ID NO: 670) TTR-756 Target:5′-TTCATTCCACTTTAACTTGATTTTTTA-3′ (SEQ ID NO: 1054)5′-UCAUUCCACUUUAACUUGAUUUUUUAA-3′ (SEQ ID NO: 2207)3′-AGUAAGGUGAAAUUGAACUAAAAAAUU-5′ (SEQ ID NO: 671) TTR-757 Target:5′-TCATTCCACTTTAACTTGATTTTTTAA-3′ (SEQ ID NO: 1055)5′-CAUUCCACUUUAACUUGAUUUUUUAAA-3′ (SEQ ID NO: 2208)3′-GUAAGGUGAAAUUGAACUAAAAAAUUU-5′ (SEQ ID NO: 672) TTR-758 Target:5′-CATTCCACTTTAACTTGATTTTTTAAA-3′ (SEQ ID NO: 1056)5′-AUUCCACUUUAACUUGAUUUUUUAAAU-3′ (SEQ ID NO: 2209)3′-UAAGGUGAAAUUGAACUAAAAAAUUUA-5′ (SEQ ID NO: 673) TTR-759 Target:5′-ATTCCACTTTAACTTGATTTTTTAAAT-3′ (SEQ ID NO: 1057)5′-UUCCACUUUAACUUGAUUUUUUAAAUU-3′ (SEQ ID NO: 2210)3′-AAGGUGAAAUUGAACUAAAAAAUUUAA-5′ (SEQ ID NO: 674) TTR-760 Target:5′-TTCCACTTTAACTTGATTTTTTAAATT-3′ (SEQ ID NO: 1058)5′-UCCACUUUAACUUGAUUUUUUAAAUUC-3′ (SEQ ID NO: 2211)3′-AGGUGAAAUUGAACUAAAAAAUUUAAG-5′ (SEQ ID NO: 675) TTR-761 Target:5′-TCCACTTTAACTTGATTTTTTAAATTC-3′ (SEQ ID NO: 1059)5′-CCACUUUAACUUGAUUUUUUAAAUUCC-3′ (SEQ ID NO: 2212)3′-GGUGAAAUUGAACUAAAAAAUUUAAGG-5′ (SEQ ID NO: 676) TTR-762 Target:5′-CCACTTTAACTTGATTTTTTAAATTCC-3′ (SEQ ID NO: 1060)5′-CACUUUAACUUGAUUUUUUAAAUUCCC-3′ (SEQ ID NO: 2213)3′-GUGAAAUUGAACUAAAAAAUUUAAGGG-5′ (SEQ ID NO: 677) TTR-763 Target:5′-CACTTTAACTTGATTTTTTAAATTCCC-3′ (SEQ ID NO: 1061)5′-ACUUUAACUUGAUUUUUUAAAUUCCCU-3′ (SEQ ID NO: 2214)3′-UGAAAUUGAACUAAAAAAUUUAAGGGA-5′ (SEQ ID NO: 678) TTR-764 Target:5′-ACTTTAACTTGATTTTTTAAATTCCCT-3′ (SEQ ID NO: 1062)5′-CUUUAACUUGAUUUUUUAAAUUCCCUU-3′ (SEQ ID NO: 2215)3′-GAAAUUGAACUAAAAAAUUUAAGGGAA-5′ (SEQ ID NO: 679) TTR-765 Target:5′-CTTTAACTTGATTTTTTAAATTCCCTT-3′ (SEQ ID NO: 1063)5′-UUUAACUUGAUUUUUUAAAUUCCCUUA-3′ (SEQ ID NO: 2216)3′-AAAUUGAACUAAAAAAUUUAAGGGAAU-5′ (SEQ ID NO: 680) TTR-766 Target:5′-TTTAACTTGATTTTTTAAATTCCCTTA-3′ (SEQ ID NO: 1064)5′-UUAACUUGAUUUUUUAAAUUCCCUUAU-3′ (SEQ ID NO: 2217)3′-AAUUGAACUAAAAAAUUUAAGGGAAUA-5′ (SEQ ID NO: 681) TTR-767 Target:5′-TTAACTTGATTTTTTAAATTCCCTTAT-3′ (SEQ ID NO: 1065)5′-UAACUUGAUUUUUUAAAUUCCCUUAUU-3′ (SEQ ID NO: 2218)3′-AUUGAACUAAAAAAUUUAAGGGAAUAA-5′ (SEQ ID NO: 682) TTR-768 Target:5′-TAACTTGATTTTTTAAATTCCCTTATT-3′ (SEQ ID NO: 1066)5′-AACUUGAUUUUUUAAAUUCCCUUAUUG-3′ (SEQ ID NO: 2219)3′-UUGAACUAAAAAAUUUAAGGGAAUAAC-5′ (SEQ ID NO: 683) TTR-769 Target:5′-AACTTGATTTTTTAAATTCCCTTATTG-3′ (SEQ ID NO: 1067)5′-ACUUGAUUUUUUAAAUUCCCUUAUUGU-3′ (SEQ ID NO: 2220)3′-UGAACUAAAAAAUUUAAGGGAAUAACA-5′ (SEQ ID NO: 684) TTR-770 Target:5′-ACTTGATTTTTTAAATTCCCTTATTGT-3′ (SEQ ID NO: 1068)5′-CUUGAUUUUUUAAAUUCCCUUAUUGUC-3′ (SEQ ID NO: 2221)3′-GAACUAAAAAAUUUAAGGGAAUAACAG-5′ (SEQ ID NO: 685) TTR-771 Target:5′-CTTGATTTTTTAAATTCCCTTATTGTC-3′ (SEQ ID NO: 1069)5′-UUGAUUUUUUAAAUUCCCUUAUUGUCC-3′ (SEQ ID NO: 2222)3′-AACUAAAAAAUUUAAGGGAAUAACAGG-5′ (SEQ ID NO: 686) TTR-772 Target:5′-TTGATTTTTTAAATTCCCTTATTGTCC-3′ (SEQ ID NO: 1070)5′-UGAUUUUUUAAAUUCCCUUAUUGUCCC-3′ (SEQ ID NO: 2223)3′-ACUAAAAAAUUUAAGGGAAUAACAGGG-5′ (SEQ ID NO: 687) TTR-773 Target:5′-TGATTTTTTAAATTCCCTTATTGTCCC-3′ (SEQ ID NO: 1071)5′-AUUUUUUAAAUUCCCUUAUUGUCCCUU-3′ (SEQ ID NO: 2224)3′-UAAAAAAUUUAAGGGAAUAACAGGGAA-5′ (SEQ ID NO: 688) TTR-775 Target:5′-ATTTTTTAAATTCCCTTATTGTCCCTT-3′ (SEQ ID NO: 1072)5′-UUAAAUUCCCUUAUUGUCCCUUCCAAA-3′ (SEQ ID NO: 2225)3′-AAUUUAAGGGAAUAACAGGGAAGGUUU-5′ (SEQ ID NO: 689) TTR-780 Target:5′-TTAAATTCCCTTATTGTCCCTTCCAAA-3′ (SEQ ID NO: 1073)5′-UAAAUUCCCUUAUUGUCCCUUCCAAAA-3′ (SEQ ID NO: 2226)3′-AUUUAAGGGAAUAACAGGGAAGGUUUU-5′ (SEQ ID NO: 690) TTR-781 Target:5′-TAAATTCCCTTATTGTCCCTTCCAAAA-3′ (SEQ ID NO: 1074)5′-AUUCCCUUAUUGUCCCUUCCAAAAAAA-3′ (SEQ ID NO: 2227)3′-UAAGGGAAUAACAGGGAAGGUUUUUUU-5′ (SEQ ID NO: 691) TTR-784 Target:5′-ATTCCCTTATTGTCCCTTCCAAAAAAA-3′ (SEQ ID NO: 1075)5′-AAAAAAAGAGAAUCAAAAUUUUACAAA-3′ (SEQ ID NO: 2228)3′-UUUUUUUCUCUUAGUUUUAAAAUGUUU-5′ (SEQ ID NO: 692) TTR-805 Target:5′-AAAAAAAGAGAATCAAAATTTTACAAA-3′ (SEQ ID NO: 1076)5′-AAAAAAGAGAAUCAAAAUUUUACAAAG-3′ (SEQ ID NO: 2229)3′-UUUUUUCUCUUAGUUUUAAAAUGUUUC-5′ (SEQ ID NO: 693) TTR-806 Target:5′-AAAAAAGAGAATCAAAATTTTACAAAG-3′ (SEQ ID NO: 1077)5′-AAAAAGAGAAUCAAAAUUUUACAAAGA-3′ (SEQ ID NO: 2230)3′-UUUUUCUCUUAGUUUUAAAAUGUUUCU-5′ (SEQ ID NO: 694) TTR-807 Target:5′-AAAAAGAGAATCAAAATTTTACAAAGA-3′ (SEQ ID NO: 1078)5′-AAAAGAGAAUCAAAAUUUUACAAAGAA-3′ (SEQ ID NO: 2231)3′-UUUUCUCUUAGUUUUAAAAUGUUUCUU-5′ (SEQ ID NO: 695) TTR-808 Target:5′-AAAAGAGAATCAAAATTTTACAAAGAA-3′ (SEQ ID NO: 1079)5′-AAAGAGAAUCAAAAUUUUACAAAGAAU-3′ (SEQ ID NO: 2232)3′-UUUCUCUUAGUUUUAAAAUGUUUCUUA-5′ (SEQ ID NO: 696) TTR-809 Target:5′-AAAGAGAATCAAAATTTTACAAAGAAT-3′ (SEQ ID NO: 1080)5′-AAGAGAAUCAAAAUUUUACAAAGAAUC-3′ (SEQ ID NO: 2233)3′-UUCUCUUAGUUUUAAAAUGUUUCUUAG-5′ (SEQ ID NO: 697) TTR-810 Target:5′-AAGAGAATCAAAATTTTACAAAGAATC-3′ (SEQ ID NO: 1081)5′-AGAGAAUCAAAAUUUUACAAAGAAUCA-3′ (SEQ ID NO: 2234)3′-UCUCUUAGUUUUAAAAUGUUUCUUAGU-5′ (SEQ ID NO: 698) TTR-811 Target:5′-AGAGAATCAAAATTTTACAAAGAATCA-3′ (SEQ ID NO: 1082)5′-GAGAAUCAAAAUUUUACAAAGAAUCAA-3′ (SEQ ID NO: 2235)3′-CUCUUAGUUUUAAAAUGUUUCUUAGUU-5′ (SEQ ID NO: 699) TTR-812 Target:5′-GAGAATCAAAATTTTACAAAGAATCAA-3′ (SEQ ID NO: 1083)5′-AGAAUCAAAAUUUUACAAAGAAUCAAA-3′ (SEQ ID NO: 2236)3′-UCUUAGUUUUAAAAUGUUUCUUAGUUU-5′ (SEQ ID NO: 700) TTR-813 Target:5′-AGAATCAAAATTTTACAAAGAATCAAA-3′ (SEQ ID NO: 1084)5′-GAAUCAAAAUUUUACAAAGAAUCAAAG-3′ (SEQ ID NO: 2237)3′-CUUAGUUUUAAAAUGUUUCUUAGUUUC-5′ (SEQ ID NO: 701) TTR-814 Target:5′-GAATCAAAATTTTACAAAGAATCAAAG-3′ (SEQ ID NO: 1085)5′-AAUCAAAAUUUUACAAAGAAUCAAAGG-3′ (SEQ ID NO: 2238)3′-UUAGUUUUAAAAUGUUUCUUAGUUUCC-5′ (SEQ ID NO: 702) TTR-815 Target:5′-AATCAAAATTTTACAAAGAATCAAAGG-3′ (SEQ ID NO: 1086)5′-AUCAAAAUUUUACAAAGAAUCAAAGGA-3′ (SEQ ID NO: 2239)3′-UAGUUUUAAAAUGUUUCUUAGUUUCCU-5′ (SEQ ID NO: 703) TTR-816 Target:5′-ATCAAAATTTTACAAAGAATCAAAGGA-3′ (SEQ ID NO: 1087)5′-UCAAAAUUUUACAAAGAAUCAAAGGAA-3′ (SEQ ID NO: 2240)3′-AGUUUUAAAAUGUUUCUUAGUUUCCUU-5′ (SEQ ID NO: 704) TTR-817 Target:5′-TCAAAATTTTACAAAGAATCAAAGGAA-3′ (SEQ ID NO: 1088)5′-CAAAAUUUUACAAAGAAUCAAAGGAAU-3′ (SEQ ID NO: 2241)3′-GUUUUAAAAUGUUUCUUAGUUUCCUUA-5′ (SEQ ID NO: 705) TTR-818 Target:5′-CAAAATTTTACAAAGAATCAAAGGAAT-3′ (SEQ ID NO: 1089)5′-AAAAUUUUACAAAGAAUCAAAGGAAUU-3′ (SEQ ID NO: 2242)3′-UUUUAAAAUGUUUCUUAGUUUCCUUAA-5′ (SEQ ID NO: 706) TTR-819 Target:5′-AAAATTTTACAAAGAATCAAAGGAATT-3′ (SEQ ID NO: 1090)5′-AAUUUUACAAAGAAUCAAAGGAAUUCU-3′ (SEQ ID NO: 2243)3′-UUAAAAUGUUUCUUAGUUUCCUUAAGA-5′ (SEQ ID NO: 707) TTR-821 Target:5′-AATTTTACAAAGAATCAAAGGAATTCT-3′ (SEQ ID NO: 1091)5′-AUUUUACAAAGAAUCAAAGGAAUUCUA-3′ (SEQ ID NO: 2244)3′-UAAAAUGUUUCUUAGUUUCCUUAAGAU-5′ (SEQ ID NO: 708) TTR-822 Target:5′-ATTTTACAAAGAATCAAAGGAATTCTA-3′ (SEQ ID NO: 1092)5′-UUUUACAAAGAAUCAAAGGAAUUCUAG-3′ (SEQ ID NO: 2245)3′-AAAAUGUUUCUUAGUUUCCUUAAGAUC-5′ (SEQ ID NO: 709) TTR-823 Target:5′-TTTTACAAAGAATCAAAGGAATTCTAG-3′ (SEQ ID NO: 1093)5′-UUUACAAAGAAUCAAAGGAAUUCUAGA-3′ (SEQ ID NO: 2246)3′-AAAUGUUUCUUAGUUUCCUUAAGAUCU-5′ (SEQ ID NO: 710) TTR-824 Target:5′-TTTACAAAGAATCAAAGGAATTCTAGA-3′ (SEQ ID NO: 1094)5′-UUACAAAGAAUCAAAGGAAUUCUAGAA-3′ (SEQ ID NO: 2247)3′-AAUGUUUCUUAGUUUCCUUAAGAUCUU-5′ (SEQ ID NO: 711) TTR-825 Target:5′-TTACAAAGAATCAAAGGAATTCTAGAA-3′ (SEQ ID NO: 1095)5′-UACAAAGAAUCAAAGGAAUUCUAGAAA-3′ (SEQ ID NO: 2248)3′-AUGUUUCUUAGUUUCCUUAAGAUCUUU-5′ (SEQ ID NO: 712) TTR-826 Target:5′-TACAAAGAATCAAAGGAATTCTAGAAA-3′ (SEQ ID NO: 1096)5′-ACAAAGAAUCAAAGGAAUUCUAGAAAG-3′ (SEQ ID NO: 2249)3′-UGUUUCUUAGUUUCCUUAAGAUCUUUC-5′ (SEQ ID NO: 713) TTR-827 Target:5′-ACAAAGAATCAAAGGAATTCTAGAAAG-3′ (SEQ ID NO: 1097)5′-CAAAGAAUCAAAGGAAUUCUAGAAAGU-3′ (SEQ ID NO: 2250)3′-GUUUCUUAGUUUCCUUAAGAUCUUUCA-5′ (SEQ ID NO: 714) TTR-828 Target:5′-CAAAGAATCAAAGGAATTCTAGAAAGT-3′ (SEQ ID NO: 1098)5′-AAAGAAUCAAAGGAAUUCUAGAAAGUA-3′ (SEQ ID NO: 2251)3′-UUUCUUAGUUUCCUUAAGAUCUUUCAU-5′ (SEQ ID NO: 715) TTR-829 Target:5′-AAAGAATCAAAGGAATTCTAGAAAGTA-3′ (SEQ ID NO: 1099)5′-AAGAAUCAAAGGAAUUCUAGAAAGUAU-3′ (SEQ ID NO: 2252)3′-UUCUUAGUUUCCUUAAGAUCUUUCAUA-5′ (SEQ ID NO: 716) TTR-830 Target:5′-AAGAATCAAAGGAATTCTAGAAAGTAT-3′ (SEQ ID NO: 1100)5′-AGAAUCAAAGGAAUUCUAGAAAGUAUC-3′ (SEQ ID NO: 2253)3′-UCUUAGUUUCCUUAAGAUCUUUCAUAG-5′ (SEQ ID NO: 717) TTR-831 Target:5′-AGAATCAAAGGAATTCTAGAAAGTATC-3′ (SEQ ID NO: 1101)5′-GAAUCAAAGGAAUUCUAGAAAGUAUCU-3′ (SEQ ID NO: 2254)3′-CUUAGUUUCCUUAAGAUCUUUCAUAGA-5′ (SEQ ID NO: 718) TTR-832 Target:5′-GAATCAAAGGAATTCTAGAAAGTATCT-3′ (SEQ ID NO: 1102)5′-AAUCAAAGGAAUUCUAGAAAGUAUCUG-3′ (SEQ ID NO: 2255)3′-UUAGUUUCCUUAAGAUCUUUCAUAGAC-5′ (SEQ ID NO: 719) TTR-833 Target:5′-AATCAAAGGAATTCTAGAAAGTATCTG-3′ (SEQ ID NO: 1103)5′-AUCAAAGGAAUUCUAGAAAGUAUCUGG-3′ (SEQ ID NO: 2256)3′-UAGUUUCCUUAAGAUCUUUCAUAGACC-5′ (SEQ ID NO: 720) TTR-834 Target:5′-ATCAAAGGAATTCTAGAAAGTATCTGG-3′ (SEQ ID NO: 1104)5′-UCAAAGGAAUUCUAGAAAGUAUCUGGG-3′ (SEQ ID NO: 2257)3′-AGUUUCCUUAAGAUCUUUCAUAGACCC-5′ (SEQ ID NO: 721) TTR-835 Target:5′-TCAAAGGAATTCTAGAAAGTATCTGGG-3′ (SEQ ID NO: 1105)5′-CUAGGAGAGAUCCAAAUUUCCAUUGUC-3′ (SEQ ID NO: 2258)3′-GAUCCUCUCUAGGUUUAAAGGUAACAG-5′ (SEQ ID NO: 722) TTR-869 Target:5′-CTAGGAGAGATCCAAATTTCCATTGTC-3′ (SEQ ID NO: 1106)5′-UAGGAGAGAUCCAAAUUUCCAUUGUCU-3′ (SEQ ID NO: 2259)3′-AUCCUCUCUAGGUUUAAAGGUAACAGA-5′ (SEQ ID NO: 723) TTR-870 Target:5′-TAGGAGAGATCCAAATTTCCATTGTCT-3′ (SEQ ID NO: 1107)5′-GAGAGAUCCAAAUUUCCAUUGUCUUGC-3′ (SEQ ID NO: 2260)3′-CUCUCUAGGUUUAAAGGUAACAGAACG-5′ (SEQ ID NO: 724) TTR-873 Target:5′-GAGAGATCCAAATTTCCATTGTCTTGC-3′ (SEQ ID NO: 1108)5′-AGAGAUCCAAAUUUCCAUUGUCUUGCA-3′ (SEQ ID NO: 2261)3′-UCUCUAGGUUUAAAGGUAACAGAACGU-5′ (SEQ ID NO: 725) TTR-874 Target:5′-AGAGATCCAAATTTCCATTGTCTTGCA-3′ (SEQ ID NO: 1109)5′-GAGAUCCAAAUUUCCAUUGUCUUGCAA-3′ (SEQ ID NO: 2262)3′-CUCUAGGUUUAAAGGUAACAGAACGUU-5′ (SEQ ID NO: 726) TTR-875 Target:5′-GAGATCCAAATTTCCATTGTCTTGCAA-3′ (SEQ ID NO: 1110)5′-AGAUCCAAAUUUCCAUUGUCUUGCAAG-3′ (SEQ ID NO: 2263)3′-UCUAGGUUUAAAGGUAACAGAACGUUC-5′ (SEQ ID NO: 727) TTR-876 Target:5′-AGATCCAAATTTCCATTGTCTTGCAAG-3′ (SEQ ID NO: 1111)5′-GAUCCAAAUUUCCAUUGUCUUGCAAGC-3′ (SEQ ID NO: 2264)3′-CUAGGUUUAAAGGUAACAGAACGUUCG-5′ (SEQ ID NO: 728) TTR-877 Target:5′-GATCCAAATTTCCATTGTCTTGCAAGC-3′ (SEQ ID NO: 1112)5′-AUCCAAAUUUCCAUUGUCUUGCAAGCA-3′ (SEQ ID NO: 2265)3′-UAGGUUUAAAGGUAACAGAACGUUCGU-5′ (SEQ ID NO: 729) TTR-878 Target:5′-ATCCAAATTTCCATTGTCTTGCAAGCA-3′ (SEQ ID NO: 1113)5′-UCCAAAUUUCCAUUGUCUUGCAAGCAA-3′ (SEQ ID NO: 2266)3′-AGGUUUAAAGGUAACAGAACGUUCGUU-5′ (SEQ ID NO: 730) TTR-879 Target:5′-TCCAAATTTCCATTGTCTTGCAAGCAA-3′ (SEQ ID NO: 1114)5′-CCAAAUUUCCAUUGUCUUGCAAGCAAA-3′ (SEQ ID NO: 2267)3′-GGUUUAAAGGUAACAGAACGUUCGUUU-5′ (SEQ ID NO: 731) TTR-880 Target:5′-CCAAATTTCCATTGTCTTGCAAGCAAA-3′ (SEQ ID NO: 1115)5′-CAAAUUUCCAUUGUCUUGCAAGCAAAG-3′ (SEQ ID NO: 2268)3′-GUUUAAAGGUAACAGAACGUUCGUUUC-5′ (SEQ ID NO: 732) TTR-881 Target:5′-CAAATTTCCATTGTCTTGCAAGCAAAG-3′ (SEQ ID NO: 1116)5′-AAAUUUCCAUUGUCUUGCAAGCAAAGC-3′ (SEQ ID NO: 2269)3′-UUUAAAGGUAACAGAACGUUCGUUUCG-5′ (SEQ ID NO: 733) TTR-882 Target:5′-AAATTTCCATTGTCTTGCAAGCAAAGC-3′ (SEQ ID NO: 1117)5′-AAUUUCCAUUGUCUUGCAAGCAAAGCA-3′ (SEQ ID NO: 2270)3′-UUAAAGGUAACAGAACGUUCGUUUCGU-5′ (SEQ ID NO: 734) TTR-883 Target:5′-AATTTCCATTGTCTTGCAAGCAAAGCA-3′ (SEQ ID NO: 1118)5′-AUUUCCAUUGUCUUGCAAGCAAAGCAC-3′ (SEQ ID NO: 2271)3′-UAAAGGUAACAGAACGUUCGUUUCGUG-5′ (SEQ ID NO: 735) TTR-884 Target:5′-ATTTCCATTGTCTTGCAAGCAAAGCAC-3′ (SEQ ID NO: 1119)5′-UUUCCAUUGUCUUGCAAGCAAAGCACG-3′ (SEQ ID NO: 2272)3′-AAAGGUAACAGAACGUUCGUUUCGUGC-5′ (SEQ ID NO: 736) TTR-885 Target:5′-TTTCCATTGTCTTGCAAGCAAAGCACG-3′ (SEQ ID NO: 1120)5′-UUCCAUUGUCUUGCAAGCAAAGCACGU-3′ (SEQ ID NO: 2273)3′-AAGGUAACAGAACGUUCGUUUCGUGCA-5′ (SEQ ID NO: 737) TTR-886 Target:5′-TTCCATTGTCTTGCAAGCAAAGCACGT-3′ (SEQ ID NO: 1121)5′-UCCAUUGUCUUGCAAGCAAAGCACGUA-3′ (SEQ ID NO: 2274)3′-AGGUAACAGAACGUUCGUUUCGUGCAU-5′ (SEQ ID NO: 738) TTR-887 Target:5′-TCCATTGTCTTGCAAGCAAAGCACGTA-3′ (SEQ ID NO: 1122)5′-CCAUUGUCUUGCAAGCAAAGCACGUAU-3′ (SEQ ID NO: 2275)3′-GGUAACAGAACGUUCGUUUCGUGCAUA-5′ (SEQ ID NO: 739) TTR-888 Target:5′-CCATTGTCTTGCAAGCAAAGCACGTAT-3′ (SEQ ID NO: 1123)5′-CAUUGUCUUGCAAGCAAAGCACGUAUU-3′ (SEQ ID NO: 2276)3′-GUAACAGAACGUUCGUUUCGUGCAUAA-5′ (SEQ ID NO: 740) TTR-889 Target:5′-CATTGTCTTGCAAGCAAAGCACGTATT-3′ (SEQ ID NO: 1124)5′-AUUGUCUUGCAAGCAAAGCACGUAUUA-3′ (SEQ ID NO: 2277)3′-UAACAGAACGUUCGUUUCGUGCAUAAU-5′ (SEQ ID NO: 741) TTR-890 Target:5′-ATTGTCTTGCAAGCAAAGCACGTATTA-3′ (SEQ ID NO: 1125)5′-UUGUCUUGCAAGCAAAGCACGUAUUAA-3′ (SEQ ID NO: 2278)3′-AACAGAACGUUCGUUUCGUGCAUAAUU-5′ (SEQ ID NO: 742) TTR-891 Target:5′-TTGTCTTGCAAGCAAAGCACGTATTAA-3′ (SEQ ID NO: 1126)5′-UGUCUUGCAAGCAAAGCACGUAUUAAA-3′ (SEQ ID NO: 2279)3′-ACAGAACGUUCGUUUCGUGCAUAAUUU-5′ (SEQ ID NO: 743) TTR-892 Target:5′-TGTCTTGCAAGCAAAGCACGTATTAAA-3′ (SEQ ID NO: 1127)5′-GUCUUGCAAGCAAAGCACGUAUUAAAU-3′ (SEQ ID NO: 2280)3′-CAGAACGUUCGUUUCGUGCAUAAUUUA-5′ (SEQ ID NO: 744) TTR-893 Target:5′-GTCTTGCAAGCAAAGCACGTATTAAAT-3′ (SEQ ID NO: 1128)5′-UCUUGCAAGCAAAGCACGUAUUAAAUA-3′ (SEQ ID NO: 2281)3′-AGAACGUUCGUUUCGUGCAUAAUUUAU-5′ (SEQ ID NO: 745) TTR-894 Target:5′-TCTTGCAAGCAAAGCACGTATTAAATA-3′ (SEQ ID NO: 1129)5′-CUUGCAAGCAAAGCACGUAUUAAAUAU-3′ (SEQ ID NO: 2282)3′-GAACGUUCGUUUCGUGCAUAAUUUAUA-5′ (SEQ ID NO: 746) TTR-895 Target:5′-CTTGCAAGCAAAGCACGTATTAAATAT-3′ (SEQ ID NO: 1130)5′-UUGCAAGCAAAGCACGUAUUAAAUAUG-3′ (SEQ ID NO: 2283)3′-AACGUUCGUUUCGUGCAUAAUUUAUAC-5′ (SEQ ID NO: 747) TTR-896 Target:5′-TTGCAAGCAAAGCACGTATTAAATATG-3′ (SEQ ID NO: 1131)5′-UGCAAGCAAAGCACGUAUUAAAUAUGA-3′ (SEQ ID NO: 2284)3′-ACGUUCGUUUCGUGCAUAAUUUAUACU-5′ (SEQ ID NO: 748) TTR-897 Target:5′-TGCAAGCAAAGCACGTATTAAATATGA-3′ (SEQ ID NO: 1132)5′-GCAAGCAAAGCACGUAUUAAAUAUGAU-3′ (SEQ ID NO: 2285)3′-CGUUCGUUUCGUGCAUAAUUUAUACUA-5′ (SEQ ID NO: 749) TTR-898 Target:5′-GCAAGCAAAGCACGTATTAAATATGAT-3′ (SEQ ID NO: 1133)5′-CAAGCAAAGCACGUAUUAAAUAUGAUC-3′ (SEQ ID NO: 2286)3′-GUUCGUUUCGUGCAUAAUUUAUACUAG-5′ (SEQ ID NO: 750) TTR-899 Target:5′-CAAGCAAAGCACGTATTAAATATGATC-3′ (SEQ ID NO: 1134)5′-AAGCAAAGCACGUAUUAAAUAUGAUCU-3′ (SEQ ID NO: 2287)3′-UUCGUUUCGUGCAUAAUUUAUACUAGA-5′ (SEQ ID NO: 751) TTR-900 Target:5′-AAGCAAAGCACGTATTAAATATGATCT-3′ (SEQ ID NO: 1135)5′-AGCAAAGCACGUAUUAAAUAUGAUCUG-3′ (SEQ ID NO: 2288)3′-UCGUUUCGUGCAUAAUUUAUACUAGAC-5′ (SEQ ID NO: 752) TTR-901 Target:5′-AGCAAAGCACGTATTAAATATGATCTG-3′ (SEQ ID NO: 1136)5′-GCAAAGCACGUAUUAAAUAUGAUCUGC-3′ (SEQ ID NO: 2289)3′-CGUUUCGUGCAUAAUUUAUACUAGACG-5′ (SEQ ID NO: 753) TTR-902 Target:5′-GCAAAGCACGTATTAAATATGATCTGC-3′ (SEQ ID NO: 1137)5′-CAAAGCACGUAUUAAAUAUGAUCUGCA-3′ (SEQ ID NO: 2290)3′-GUUUCGUGCAUAAUUUAUACUAGACGU-5′ (SEQ ID NO: 754) TTR-903 Target:5′-CAAAGCACGTATTAAATATGATCTGCA-3′ (SEQ ID NO: 1138)5′-AAAGCACGUAUUAAAUAUGAUCUGCAG-3′ (SEQ ID NO: 2291)3′-UUUCGUGCAUAAUUUAUACUAGACGUC-5′ (SEQ ID NO: 755) TTR-904 Target:5′-AAAGCACGTATTAAATATGATCTGCAG-3′ (SEQ ID NO: 1139)5′-AAGCACGUAUUAAAUAUGAUCUGCAGC-3′ (SEQ ID NO: 2292)3′-UUCGUGCAUAAUUUAUACUAGACGUCG-5′ (SEQ ID NO: 756) TTR-905 Target:5′-AAGCACGTATTAAATATGATCTGCAGC-3′ (SEQ ID NO: 1140)5′-AGCACGUAUUAAAUAUGAUCUGCAGCC-3′ (SEQ ID NO: 2293)3′-UCGUGCAUAAUUUAUACUAGACGUCGG-5′ (SEQ ID NO: 757) TTR-906 Target:5′-AGCACGTATTAAATATGATCTGCAGCC-3′ (SEQ ID NO: 1141)5′-CACGUAUUAAAUAUGAUCUGCAGCCAU-3′ (SEQ ID NO: 2294)3′-GUGCAUAAUUUAUACUAGACGUCGGUA-5′ (SEQ ID NO: 758) TTR-908 Target:5′-CACGTATTAAATATGATCTGCAGCCAT-3′ (SEQ ID NO: 1142)5′-ACGUAUUAAAUAUGAUCUGCAGCCAUU-3′ (SEQ ID NO: 2295)3′-UGCAUAAUUUAUACUAGACGUCGGUAA-5′ (SEQ ID NO: 759) TTR-909 Target:5′-ACGTATTAAATATGATCTGCAGCCATT-3′ (SEQ ID NO: 1143)5′-GUAUUAAAUAUGAUCUGCAGCCAUUAA-3′ (SEQ ID NO: 2296)3′-CAUAAUUUAUACUAGACGUCGGUAAUU-5′ (SEQ ID NO: 760) TTR-911 Target:5′-GTATTAAATATGATCTGCAGCCATTAA-3′ (SEQ ID NO: 1144)5′-UAUUAAAUAUGAUCUGCAGCCAUUAAA-3′ (SEQ ID NO: 2297)3′-AUAAUUUAUACUAGACGUCGGUAAUUU-5′ (SEQ ID NO: 761) TTR-912 Target:5′-TATTAAATATGATCTGCAGCCATTAAA-3′ (SEQ ID NO: 1145)5′-AUUAAAUAUGAUCUGCAGCCAUUAAAA-3′ (SEQ ID NO: 2298)3′-UAAUUUAUACUAGACGUCGGUAAUUUU-5′ (SEQ ID NO: 762) TTR-913 Target:5′-ATTAAATATGATCTGCAGCCATTAAAA-3′ (SEQ ID NO: 1146)5′-UUAAAUAUGAUCUGCAGCCAUUAAAAA-3′ (SEQ ID NO: 2299)3′-AAUUUAUACUAGACGUCGGUAAUUUUU-5′ (SEQ ID NO: 763) TTR-914 Target:5′-TTAAATATGATCTGCAGCCATTAAAAA-3′ (SEQ ID NO: 1147)5′-UAAAUAUGAUCUGCAGCCAUUAAAAAG-3′ (SEQ ID NO: 2300)3′-AUUUAUACUAGACGUCGGUAAUUUUUC-5′ (SEQ ID NO: 764) TTR-915 Target:5′-TAAATATGATCTGCAGCCATTAAAAAG-3′ (SEQ ID NO: 1148)5′-AAAUAUGAUCUGCAGCCAUUAAAAAGA-3′ (SEQ ID NO: 2301)3′-UUUAUACUAGACGUCGGUAAUUUUUCU-5′ (SEQ ID NO: 765) TTR-916 Target:5′-AAATATGATCTGCAGCCATTAAAAAGA-3′ (SEQ ID NO: 1149)5′-AAUAUGAUCUGCAGCCAUUAAAAAGAC-3′ (SEQ ID NO: 2302)3′-UUAUACUAGACGUCGGUAAUUUUUCUG-5′ (SEQ ID NO: 766) TTR-917 Target:5′-AATATGATCTGCAGCCATTAAAAAGAC-3′ (SEQ ID NO: 1150)5′-AUAUGAUCUGCAGCCAUUAAAAAGACA-3′ (SEQ ID NO: 2303)3′-UAUACUAGACGUCGGUAAUUUUUCUGU-5′ (SEQ ID NO: 767) TTR-918 Target:5′-ATATGATCTGCAGCCATTAAAAAGACA-3′ (SEQ ID NO: 1151)5′-UAUGAUCUGCAGCCAUUAAAAAGACAC-3′ (SEQ ID NO: 2304)3′-AUACUAGACGUCGGUAAUUUUUCUGUG-5′ (SEQ ID NO: 768) TTR-919 Target:5′-TATGATCTGCAGCCATTAAAAAGACAC-3′ (SEQ ID NO: 1152)

TABLE 6 DsiRNA Component 19 Nucleotide Target Sequences inTransthyretin mRNA TTR-27 19 nt Target #1: 5′-UGACUAAGUCAAUAAUCAG-3′(SEQ ID NO: 2305) TTR-27 19 nt Target #2: 5′-UUGACUAAGUCAAUAAUCA-3′(SEQ ID NO: 2689) TTR-27 19 nt Target #3: 5′-GUUGACUAAGUCAAUAAUC-3′(SEQ ID NO: 3073) TTR-28 19 nt Target #1: 5′-GACUAAGUCAAUAAUCAGA-3′(SEQ ID NO: 2306) TTR-28 19 nt Target #2: 5′-UGACUAAGUCAAUAAUCAG-3′(SEQ ID NO: 2690) TTR-28 19 nt Target #3: 5′-UUGACUAAGUCAAUAAUCA-3′(SEQ ID NO: 3074) TTR-29 19 nt Target #1: 5′-ACUAAGUCAAUAAUCAGAA-3′(SEQ ID NO: 2307) TTR-29 19 nt Target #2: 5′-GACUAAGUCAAUAAUCAGA-3′(SEQ ID NO: 2691) TTR-29 19 nt Target #3: 5′-UGACUAAGUCAAUAAUCAG-3′(SEQ ID NO: 3075) TTR-30 19 nt Target #1: 5′-CUAAGUCAAUAAUCAGAAU-3′(SEQ ID NO: 2308) TTR-30 19 nt Target #2: 5′-ACUAAGUCAAUAAUCAGAA-3′(SEQ ID NO: 2692) TTR-30 19 nt Target #3: 5′-GACUAAGUCAAUAAUCAGA-3′(SEQ ID NO: 3076) TTR-31 19 nt Target #1: 5′-UAAGUCAAUAAUCAGAAUC-3′(SEQ ID NO: 2309) TTR-31 19 nt Target #2: 5′-CUAAGUCAAUAAUCAGAAU-3′(SEQ ID NO: 2693) TTR-31 19 nt Target #3: 5′-ACUAAGUCAAUAAUCAGAA-3′(SEQ ID NO: 3077) TTR-32 19 nt Target #1: 5′-AAGUCAAUAAUCAGAAUCA-3′(SEQ ID NO: 2310) TTR-32 19 nt Target #2: 5′-UAAGUCAAUAAUCAGAAUC-3′(SEQ ID NO: 2694) TTR-32 19 nt Target #3: 5′-CUAAGUCAAUAAUCAGAAU-3′(SEQ ID NO: 3078) TTR-33 19 nt Target #1: 5′-AGUCAAUAAUCAGAAUCAG-3′(SEQ ID NO: 2311) TTR-33 19 nt Target #2: 5′-AAGUCAAUAAUCAGAAUCA-3′(SEQ ID NO: 2695) TTR-33 19 nt Target #3: 5′-UAAGUCAAUAAUCAGAAUC-3′(SEQ ID NO: 3079) TTR-34 19 nt Target #1: 5′-GUCAAUAAUCAGAAUCAGC-3′(SEQ ID NO: 2312) TTR-34 19 nt Target #2: 5′-AGUCAAUAAUCAGAAUCAG-3′(SEQ ID NO: 2696) TTR-34 19 nt Target #3: 5′-AAGUCAAUAAUCAGAAUCA-3′(SEQ ID NO: 3080) TTR-35 19 nt Target #1: 5′-UCAAUAAUCAGAAUCAGCA-3′(SEQ ID NO: 2313) TTR-35 19 nt Target #2: 5′-GUCAAUAAUCAGAAUCAGC-3′(SEQ ID NO: 2697) TTR-35 19 nt Target #3: 5′-AGUCAAUAAUCAGAAUCAG-3′(SEQ ID NO: 3081) TTR-36 19 nt Target #1: 5′-CAAUAAUCAGAAUCAGCAG-3′(SEQ ID NO: 2314) TTR-36 19 nt Target #2: 5′-UCAAUAAUCAGAAUCAGCA-3′(SEQ ID NO: 2698) TTR-36 19 nt Target #3: 5′-GUCAAUAAUCAGAAUCAGC-3′(SEQ ID NO: 3082) TTR-37 19 nt Target #1: 5′-AAUAAUCAGAAUCAGCAGG-3′(SEQ ID NO: 2315) TTR-37 19 nt Target #2: 5′-CAAUAAUCAGAAUCAGCAG-3′(SEQ ID NO: 2699) TTR-37 19 nt Target #3: 5′-UCAAUAAUCAGAAUCAGCA-3′(SEQ ID NO: 3083) TTR-38 19 nt Target #1: 5′-AUAAUCAGAAUCAGCAGGU-3′(SEQ ID NO: 2316) TTR-38 19 nt Target #2: 5′-AAUAAUCAGAAUCAGCAGG-3′(SEQ ID NO: 2700) TTR-38 19 nt Target #3: 5′-CAAUAAUCAGAAUCAGCAG-3′(SEQ ID NO: 3084) TTR-39 19 nt Target #1: 5′-UAAUCAGAAUCAGCAGGUU-3′(SEQ ID NO: 2317) TTR-39 19 nt Target #2: 5′-AUAAUCAGAAUCAGCAGGU-3′(SEQ ID NO: 2701) TTR-39 19 nt Target #3: 5′-AAUAAUCAGAAUCAGCAGG-3′(SEQ ID NO: 3085) TTR-40 19 nt Target #1: 5′-AAUCAGAAUCAGCAGGUUU-3′(SEQ ID NO: 2318) TTR-40 19 nt Target #2: 5′-UAAUCAGAAUCAGCAGGUU-3′(SEQ ID NO: 2702) TTR-40 19 nt Target #3: 5′-AUAAUCAGAAUCAGCAGGU-3′(SEQ ID NO: 3086) TTR-41 19 nt Target #1: 5′-AUCAGAAUCAGCAGGUUUG-3′(SEQ ID NO: 2319) TTR-41 19 nt Target #2: 5′-AAUCAGAAUCAGCAGGUUU-3′(SEQ ID NO: 2703) TTR-41 19 nt Target #3: 5′-UAAUCAGAAUCAGCAGGUU-3′(SEQ ID NO: 3087) TTR-43 19 nt Target #1: 5′-CAGAAUCAGCAGGUUUGCA-3′(SEQ ID NO: 2320) TTR-43 19 nt Target #2: 5′-UCAGAAUCAGCAGGUUUGC-3′(SEQ ID NO: 2704) TTR-43 19 nt Target #3: 5′-AUCAGAAUCAGCAGGUUUG-3′(SEQ ID NO: 3088) TTR-44 19 nt Target #1: 5′-AGAAUCAGCAGGUUUGCAG-3′(SEQ ID NO: 2321) TTR-44 19 nt Target #2: 5′-CAGAAUCAGCAGGUUUGCA-3′(SEQ ID NO: 2705) TTR-44 19 nt Target #3: 5′-UCAGAAUCAGCAGGUUUGC-3′(SEQ ID NO: 3089) TTR-46 19 nt Target #1: 5′-AAUCAGCAGGUUUGCAGUC-3′(SEQ ID NO: 2322) TTR-46 19 nt Target #2: 5′-GAAUCAGCAGGUUUGCAGU-3′(SEQ ID NO: 2706) TTR-46 19 nt Target #3: 5′-AGAAUCAGCAGGUUUGCAG-3′(SEQ ID NO: 3090) TTR-47 19 nt Target #1: 5′-AUCAGCAGGUUUGCAGUCA-3′(SEQ ID NO: 2323) TTR-47 19 nt Target #2: 5′-AAUCAGCAGGUUUGCAGUC-3′(SEQ ID NO: 2707) TTR-47 19 nt Target #3: 5′-GAAUCAGCAGGUUUGCAGU-3′(SEQ ID NO: 3091) TTR-59 19 nt Target #1: 5′-GCAGUCAGAUUGGCAGGGA-3′(SEQ ID NO: 2324) TTR-59 19 nt Target #2: 5′-UGCAGUCAGAUUGGCAGGG-3′(SEQ ID NO: 2708) TTR-59 19 nt Target #3: 5′-UUGCAGUCAGAUUGGCAGG-3′(SEQ ID NO: 3092) TTR-84 19 nt Target #1: 5′-GCCUAGCUCAGGAGAAGUG-3′(SEQ ID NO: 2325) TTR-84 19 nt Target #2: 5′-AGCCUAGCUCAGGAGAAGU-3′(SEQ ID NO: 2709) TTR-84 19 nt Target #3: 5′-CAGCCUAGCUCAGGAGAAG-3′(SEQ ID NO: 3093) TTR-87 19 nt Target #1: 5′-UAGCUCAGGAGAAGUGAGU-3′(SEQ ID NO: 2326) TTR-87 19 nt Target #2: 5′-CUAGCUCAGGAGAAGUGAG-3′(SEQ ID NO: 2710) TTR-87 19 nt Target #3: 5′-CCUAGCUCAGGAGAAGUGA-3′(SEQ ID NO: 3094) TTR-88 19 nt Target #1: 5′-AGCUCAGGAGAAGUGAGUA-3′(SEQ ID NO: 2327) TTR-88 19 nt Target #2: 5′-UAGCUCAGGAGAAGUGAGU-3′(SEQ ID NO: 2711) TTR-88 19 nt Target #3: 5′-CUAGCUCAGGAGAAGUGAG-3′(SEQ ID NO: 3095) TTR-89 19 nt Target #1: 5′-GCUCAGGAGAAGUGAGUAU-3′(SEQ ID NO: 2328) TTR-89 19 nt Target #2: 5′-AGCUCAGGAGAAGUGAGUA-3′(SEQ ID NO: 2712) TTR-89 19 nt Target #3: 5′-UAGCUCAGGAGAAGUGAGU-3′(SEQ ID NO: 3096) TTR-90 19 nt Target #1: 5′-CUCAGGAGAAGUGAGUAUA-3′(SEQ ID NO: 2329) TTR-90 19 nt Target #2: 5′-GCUCAGGAGAAGUGAGUAU-3′(SEQ ID NO: 2713) TTR-90 19 nt Target #3: 5′-AGCUCAGGAGAAGUGAGUA-3′(SEQ ID NO: 3097) TTR-92 19 nt Target #1: 5′-CAGGAGAAGUGAGUAUAAA-3′(SEQ ID NO: 2330) TTR-92 19 nt Target #2: 5′-UCAGGAGAAGUGAGUAUAA-3′(SEQ ID NO: 2714) TTR-92 19 nt Target #3: 5′-CUCAGGAGAAGUGAGUAUA-3′(SEQ ID NO: 3098) TTR-126 19 nt Target #1: 5′-GCAGCCAUCACAGAAGUCC-3′(SEQ ID NO: 2331) TTR-126 19 nt Target #2: 5′-AGCAGCCAUCACAGAAGUC-3′(SEQ ID NO: 2715) TTR-126 19 nt Target #3: 5′-GAGCAGCCAUCACAGAAGU-3′(SEQ ID NO: 3099) TTR-127 19 nt Target #1: 5′-CAGCCAUCACAGAAGUCCA-3′(SEQ ID NO: 2332) TTR-127 19 nt Target #2: 5′-GCAGCCAUCACAGAAGUCC-3′(SEQ ID NO: 2716) TTR-127 19 nt Target #3: 5′-AGCAGCCAUCACAGAAGUC-3′(SEQ ID NO: 3100) TTR-128 19 nt Target #1: 5′-AGCCAUCACAGAAGUCCAC-3′(SEQ ID NO: 2333) TTR-128 19 nt Target #2: 5′-CAGCCAUCACAGAAGUCCA-3′(SEQ ID NO: 2717) TTR-128 19 nt Target #3: 5′-GCAGCCAUCACAGAAGUCC-3′(SEQ ID NO: 3101) TTR-129 19 nt Target #1: 5′-GCCAUCACAGAAGUCCACU-3′(SEQ ID NO: 2334) TTR-129 19 nt Target #2: 5′-AGCCAUCACAGAAGUCCAC-3′(SEQ ID NO: 2718) TTR-129 19 nt Target #3: 5′-CAGCCAUCACAGAAGUCCA-3′(SEQ ID NO: 3102) TTR-130 19 nt Target #1: 5′-CCAUCACAGAAGUCCACUC-3′(SEQ ID NO: 2335) TTR-130 19 nt Target #2: 5′-GCCAUCACAGAAGUCCACU-3′(SEQ ID NO: 2719) TTR-130 19 nt Target #3: 5′-AGCCAUCACAGAAGUCCAC-3′(SEQ ID NO: 3103) TTR-131 19 nt Target #1: 5′-CAUCACAGAAGUCCACUCA-3′(SEQ ID NO: 2336) TTR-131 19 nt Target #2: 5′-CCAUCACAGAAGUCCACUC-3′(SEQ ID NO: 2720) TTR-131 19 nt Target #3: 5′-GCCAUCACAGAAGUCCACU-3′(SEQ ID NO: 3104) TTR-132 19 nt Target #1: 5′-AUCACAGAAGUCCACUCAU-3′(SEQ ID NO: 2337) TTR-132 19 nt Target #2: 5′-CAUCACAGAAGUCCACUCA-3′(SEQ ID NO: 2721) TTR-132 19 nt Target #3: 5′-CCAUCACAGAAGUCCACUC-3′(SEQ ID NO: 3105) TTR-134 19 nt Target #1: 5′-CACAGAAGUCCACUCAUUC-3′(SEQ ID NO: 2338) TTR-134 19 nt Target #2: 5′-UCACAGAAGUCCACUCAUU-3′(SEQ ID NO: 2722) TTR-134 19 nt Target #3: 5′-AUCACAGAAGUCCACUCAU-3′(SEQ ID NO: 3106) TTR-135 19 nt Target #1: 5′-ACAGAAGUCCACUCAUUCU-3′(SEQ ID NO: 2339) TTR-135 19 nt Target #2: 5′-CACAGAAGUCCACUCAUUC-3′(SEQ ID NO: 2723) TTR-135 19 nt Target #3: 5′-UCACAGAAGUCCACUCAUU-3′(SEQ ID NO: 3107) TTR-150 19 nt Target #1: 5′-UUCUUGGCAGGAUGGCUUC-3′(SEQ ID NO: 2340) TTR-150 19 nt Target #2: 5′-AUUCUUGGCAGGAUGGCUU-3′(SEQ ID NO: 2724) TTR-150 19 nt Target #3: 5′-CAUUCUUGGCAGGAUGGCU-3′(SEQ ID NO: 3108) TTR-151 19 nt Target #1: 5′-UCUUGGCAGGAUGGCUUCU-3′(SEQ ID NO: 2341) TTR-151 19 nt Target #2: 5′-UUCUUGGCAGGAUGGCUUC-3′(SEQ ID NO: 2725) TTR-151 19 nt Target #3: 5′-AUUCUUGGCAGGAUGGCUU-3′(SEQ ID NO: 3109) TTR-152 19 nt Target #1: 5′-CUUGGCAGGAUGGCUUCUC-3′(SEQ ID NO: 2342) TTR-152 19 nt Target #2: 5′-UCUUGGCAGGAUGGCUUCU-3′(SEQ ID NO: 2726) TTR-152 19 nt Target #3: 5′-UUCUUGGCAGGAUGGCUUC-3′(SEQ ID NO: 3110) TTR-153 19 nt Target #1: 5′-UUGGCAGGAUGGCUUCUCA-3′(SEQ ID NO: 2343) TTR-153 19 nt Target #2: 5′-CUUGGCAGGAUGGCUUCUC-3′(SEQ ID NO: 2727) TTR-153 19 nt Target #3: 5′-UCUUGGCAGGAUGGCUUCU-3′(SEQ ID NO: 3111) TTR-154 19 nt Target #1: 5′-UGGCAGGAUGGCUUCUCAU-3′(SEQ ID NO: 2344) TTR-154 19 nt Target #2: 5′-UUGGCAGGAUGGCUUCUCA-3′(SEQ ID NO: 2728) TTR-154 19 nt Target #3: 5′-CUUGGCAGGAUGGCUUCUC-3′(SEQ ID NO: 3112) TTR-155 19 nt Target #1: 5′-GGCAGGAUGGCUUCUCAUC-3′(SEQ ID NO: 2345) TTR-155 19 nt Target #2: 5′-UGGCAGGAUGGCUUCUCAU-3′(SEQ ID NO: 2729) TTR-155 19 nt Target #3: 5′-UUGGCAGGAUGGCUUCUCA-3′(SEQ ID NO: 3113) TTR-156 19 nt Target #1: 5′-GCAGGAUGGCUUCUCAUCG-3′(SEQ ID NO: 2346) TTR-156 19 nt Target #2: 5′-GGCAGGAUGGCUUCUCAUC-3′(SEQ ID NO: 2730) TTR-156 19 nt Target #3: 5′-UGGCAGGAUGGCUUCUCAU-3′(SEQ ID NO: 3114) TTR-157 19 nt Target #1: 5′-CAGGAUGGCUUCUCAUCGU-3′(SEQ ID NO: 2347) TTR-157 19 nt Target #2: 5′-GCAGGAUGGCUUCUCAUCG-3′(SEQ ID NO: 2731) TTR-157 19 nt Target #3: 5′-GGCAGGAUGGCUUCUCAUC-3′(SEQ ID NO: 3115) TTR-158 19 nt Target #1: 5′-AGGAUGGCUUCUCAUCGUC-3′(SEQ ID NO: 2348) TTR-158 19 nt Target #2: 5′-CAGGAUGGCUUCUCAUCGU-3′(SEQ ID NO: 2732) TTR-158 19 nt Target #3: 5′-GCAGGAUGGCUUCUCAUCG-3′(SEQ ID NO: 3116) TTR-159 19 nt Target #1: 5′-GGAUGGCUUCUCAUCGUCU-3′(SEQ ID NO: 2349) TTR-159 19 nt Target #2: 5′-AGGAUGGCUUCUCAUCGUC-3′(SEQ ID NO: 2733) TTR-159 19 nt Target #3: 5′-CAGGAUGGCUUCUCAUCGU-3′(SEQ ID NO: 3117) TTR-160 19 nt Target #1: 5′-GAUGGCUUCUCAUCGUCUG-3′(SEQ ID NO: 2350) TTR-160 19 nt Target #2: 5′-GGAUGGCUUCUCAUCGUCU-3′(SEQ ID NO: 2734) TTR-160 19 nt Target #3: 5′-AGGAUGGCUUCUCAUCGUC-3′(SEQ ID NO: 3118) TTR-161 19 nt Target #1: 5′-AUGGCUUCUCAUCGUCUGC-3′(SEQ ID NO: 2351) TTR-161 19 nt Target #2: 5′-GAUGGCUUCUCAUCGUCUG-3′(SEQ ID NO: 2735) TTR-161 19 nt Target #3: 5′-GGAUGGCUUCUCAUCGUCU-3′(SEQ ID NO: 3119) TTR-162 19 nt Target #1: 5′-UGGCUUCUCAUCGUCUGCU-3′(SEQ ID NO: 2352) TTR-162 19 nt Target #2: 5′-AUGGCUUCUCAUCGUCUGC-3′(SEQ ID NO: 2736) TTR-162 19 nt Target #3: 5′-GAUGGCUUCUCAUCGUCUG-3′(SEQ ID NO: 3120) TTR-163 19 nt Target #1: 5′-GGCUUCUCAUCGUCUGCUC-3′(SEQ ID NO: 2353) TTR-163 19 nt Target #2: 5′-UGGCUUCUCAUCGUCUGCU-3′(SEQ ID NO: 2737) TTR-163 19 nt Target #3: 5′-AUGGCUUCUCAUCGUCUGC-3′(SEQ ID NO: 3121) TTR-164 19 nt Target #1: 5′-GCUUCUCAUCGUCUGCUCC-3′(SEQ ID NO: 2354) TTR-164 19 nt Target #2: 5′-GGCUUCUCAUCGUCUGCUC-3′(SEQ ID NO: 2738) TTR-164 19 nt Target #3: 5′-UGGCUUCUCAUCGUCUGCU-3′(SEQ ID NO: 3122) TTR-165 19 nt Target #1: 5′-CUUCUCAUCGUCUGCUCCU-3′(SEQ ID NO: 2355) TTR-165 19 nt Target #2: 5′-GCUUCUCAUCGUCUGCUCC-3′(SEQ ID NO: 2739) TTR-165 19 nt Target #3: 5′-GGCUUCUCAUCGUCUGCUC-3′(SEQ ID NO: 3123) TTR-186 19 nt Target #1: 5′-UCUGCCUUGCUGGACUGGU-3′(SEQ ID NO: 2356) TTR-186 19 nt Target #2: 5′-CUCUGCCUUGCUGGACUGG-3′(SEQ ID NO: 2740) TTR-186 19 nt Target #3: 5′-CCUCUGCCUUGCUGGACUG-3′(SEQ ID NO: 3124) TTR-187 19 nt Target #1: 5′-CUGCCUUGCUGGACUGGUA-3′(SEQ ID NO: 2357) TTR-187 19 nt Target #2: 5′-UCUGCCUUGCUGGACUGGU-3′(SEQ ID NO: 2741) TTR-187 19 nt Target #3: 5′-CUCUGCCUUGCUGGACUGG-3′(SEQ ID NO: 3125) TTR-234 19 nt Target #1: 5′-CCGGUGAAUCCAAGUGUCC-3′(SEQ ID NO: 2358) TTR-234 19 nt Target #2: 5′-ACCGGUGAAUCCAAGUGUC-3′(SEQ ID NO: 2742) TTR-234 19 nt Target #3: 5′-CACCGGUGAAUCCAAGUGU-3′(SEQ ID NO: 3126) TTR-238 19 nt Target #1: 5′-UGAAUCCAAGUGUCCUCUG-3′(SEQ ID NO: 2359) TTR-238 19 nt Target #2: 5′-GUGAAUCCAAGUGUCCUCU-3′(SEQ ID NO: 2743) TTR-238 19 nt Target #3: 5′-GGUGAAUCCAAGUGUCCUC-3′(SEQ ID NO: 3127) TTR-239 19 nt Target #1: 5′-GAAUCCAAGUGUCCUCUGA-3′(SEQ ID NO: 2360) TTR-239 19 nt Target #2: 5′-UGAAUCCAAGUGUCCUCUG-3′(SEQ ID NO: 2744) TTR-239 19 nt Target #3: 5′-GUGAAUCCAAGUGUCCUCU-3′(SEQ ID NO: 3128) TTR-240 19 nt Target #1: 5′-AAUCCAAGUGUCCUCUGAU-3′(SEQ ID NO: 2361) TTR-240 19 nt Target #2: 5′-GAAUCCAAGUGUCCUCUGA-3′(SEQ ID NO: 2745) TTR-240 19 nt Target #3: 5′-UGAAUCCAAGUGUCCUCUG-3′(SEQ ID NO: 3129) TTR-241 19 nt Target #1: 5′-AUCCAAGUGUCCUCUGAUG-3′(SEQ ID NO: 2362) TTR-241 19 nt Target #2: 5′-AAUCCAAGUGUCCUCUGAU-3′(SEQ ID NO: 2746) TTR-241 19 nt Target #3: 5′-GAAUCCAAGUGUCCUCUGA-3′(SEQ ID NO: 3130) TTR-242 19 nt Target #1: 5′-UCCAAGUGUCCUCUGAUGG-3′(SEQ ID NO: 2363) TTR-242 19 nt Target #2: 5′-AUCCAAGUGUCCUCUGAUG-3′(SEQ ID NO: 2747) TTR-242 19 nt Target #3: 5′-AAUCCAAGUGUCCUCUGAU-3′(SEQ ID NO: 3131) TTR-243 19 nt Target #1: 5′-CCAAGUGUCCUCUGAUGGU-3′(SEQ ID NO: 2364) TTR-243 19 nt Target #2: 5′-UCCAAGUGUCCUCUGAUGG-3′(SEQ ID NO: 2748) TTR-243 19 nt Target #3: 5′-AUCCAAGUGUCCUCUGAUG-3′(SEQ ID NO: 3132) TTR-244 19 nt Target #1: 5′-CAAGUGUCCUCUGAUGGUC-3′(SEQ ID NO: 2365) TTR-244 19 nt Target #2: 5′-CCAAGUGUCCUCUGAUGGU-3′(SEQ ID NO: 2749) TTR-244 19 nt Target #3: 5′-UCCAAGUGUCCUCUGAUGG-3′(SEQ ID NO: 3133) TTR-245 19 nt Target #1: 5′-AAGUGUCCUCUGAUGGUCA-3′(SEQ ID NO: 2366) TTR-245 19 nt Target #2: 5′-CAAGUGUCCUCUGAUGGUC-3′(SEQ ID NO: 2750) TTR-245 19 nt Target #3: 5′-CCAAGUGUCCUCUGAUGGU-3′(SEQ ID NO: 3134) TTR-246 19 nt Target #1: 5′-AGUGUCCUCUGAUGGUCAA-3′(SEQ ID NO: 2367) TTR-246 19 nt Target #2: 5′-AAGUGUCCUCUGAUGGUCA-3′(SEQ ID NO: 2751) TTR-246 19 nt Target #3: 5′-CAAGUGUCCUCUGAUGGUC-3′(SEQ ID NO: 3135) TTR-247 19 nt Target #1: 5′-GUGUCCUCUGAUGGUCAAA-3′(SEQ ID NO: 2368) TTR-247 19 nt Target #2: 5′-AGUGUCCUCUGAUGGUCAA-3′(SEQ ID NO: 2752) TTR-247 19 nt Target #3: 5′-AAGUGUCCUCUGAUGGUCA-3′(SEQ ID NO: 3136) TTR-248 19 nt Target #1: 5′-UGUCCUCUGAUGGUCAAAG-3′(SEQ ID NO: 2369) TTR-248 19 nt Target #2: 5′-GUGUCCUCUGAUGGUCAAA-3′(SEQ ID NO: 2753) TTR-248 19 nt Target #3: 5′-AGUGUCCUCUGAUGGUCAA-3′(SEQ ID NO: 3137) TTR-249 19 nt Target #1: 5′-GUCCUCUGAUGGUCAAAGU-3′(SEQ ID NO: 2370) TTR-249 19 nt Target #2: 5′-UGUCCUCUGAUGGUCAAAG-3′(SEQ ID NO: 2754) TTR-249 19 nt Target #3: 5′-GUGUCCUCUGAUGGUCAAA-3′(SEQ ID NO: 3138) TTR-250 19 nt Target #1: 5′-UCCUCUGAUGGUCAAAGUU-3′(SEQ ID NO: 2371) TTR-250 19 nt Target #2: 5′-GUCCUCUGAUGGUCAAAGU-3′(SEQ ID NO: 2755) TTR-250 19 nt Target #3: 5′-UGUCCUCUGAUGGUCAAAG-3′(SEQ ID NO: 3139) TTR-251 19 nt Target #1: 5′-CCUCUGAUGGUCAAAGUUC-3′(SEQ ID NO: 2372) TTR-251 19 nt Target #2: 5′-UCCUCUGAUGGUCAAAGUU-3′(SEQ ID NO: 2756) TTR-251 19 nt Target #3: 5′-GUCCUCUGAUGGUCAAAGU-3′(SEQ ID NO: 3140) TTR-252 19 nt Target #1: 5′-CUCUGAUGGUCAAAGUUCU-3′(SEQ ID NO: 2373) TTR-252 19 nt Target #2: 5′-CCUCUGAUGGUCAAAGUUC-3′(SEQ ID NO: 2757) TTR-252 19 nt Target #3: 5′-UCCUCUGAUGGUCAAAGUU-3′(SEQ ID NO: 3141) TTR-253 19 nt Target #1: 5′-UCUGAUGGUCAAAGUUCUA-3′(SEQ ID NO: 2374) TTR-253 19 nt Target #2: 5′-CUCUGAUGGUCAAAGUUCU-3′(SEQ ID NO: 2758) TTR-253 19 nt Target #3: 5′-CCUCUGAUGGUCAAAGUUC-3′(SEQ ID NO: 3142) TTR-254 19 nt Target #1: 5′-CUGAUGGUCAAAGUUCUAG-3′(SEQ ID NO: 2375) TTR-254 19 nt Target #2: 5′-UCUGAUGGUCAAAGUUCUA-3′(SEQ ID NO: 2759) TTR-254 19 nt Target #3: 5′-CUCUGAUGGUCAAAGUUCU-3′(SEQ ID NO: 3143) TTR-255 19 nt Target #1: 5′-UGAUGGUCAAAGUUCUAGA-3′(SEQ ID NO: 2376) TTR-255 19 nt Target #2: 5′-CUGAUGGUCAAAGUUCUAG-3′(SEQ ID NO: 2760) TTR-255 19 nt Target #3: 5′-UCUGAUGGUCAAAGUUCUA-3′(SEQ ID NO: 3144) TTR-256 19 nt Target #1: 5′-GAUGGUCAAAGUUCUAGAU-3′(SEQ ID NO: 2377) TTR-256 19 nt Target #2: 5′-UGAUGGUCAAAGUUCUAGA-3′(SEQ ID NO: 2761) TTR-256 19 nt Target #3: 5′-CUGAUGGUCAAAGUUCUAG-3′(SEQ ID NO: 3145) TTR-257 19 nt Target #1: 5′-AUGGUCAAAGUUCUAGAUG-3′(SEQ ID NO: 2378) TTR-257 19 nt Target #2: 5′-GAUGGUCAAAGUUCUAGAU-3′(SEQ ID NO: 2762) TTR-257 19 nt Target #3: 5′-UGAUGGUCAAAGUUCUAGA-3′(SEQ ID NO: 3146) TTR-258 19 nt Target #1: 5′-UGGUCAAAGUUCUAGAUGC-3′(SEQ ID NO: 2379) TTR-258 19 nt Target #2: 5′-AUGGUCAAAGUUCUAGAUG-3′(SEQ ID NO: 2763) TTR-258 19 nt Target #3: 5′-GAUGGUCAAAGUUCUAGAU-3′(SEQ ID NO: 3147) TTR-346 19 nt Target #1: 5′-GCCAUUUGCCUCUGGGAAA-3′(SEQ ID NO: 2380) TTR-346 19 nt Target #2: 5′-AGCCAUUUGCCUCUGGGAA-3′(SEQ ID NO: 2764) TTR-346 19 nt Target #3: 5′-GAGCCAUUUGCCUCUGGGA-3′(SEQ ID NO: 3148) TTR-347 19 nt Target #1: 5′-CCAUUUGCCUCUGGGAAAA-3′(SEQ ID NO: 2381) TTR-347 19 nt Target #2: 5′-GCCAUUUGCCUCUGGGAAA-3′(SEQ ID NO: 2765) TTR-347 19 nt Target #3: 5′-AGCCAUUUGCCUCUGGGAA-3′(SEQ ID NO: 3149) TTR-348 19 nt Target #1: 5′-CAUUUGCCUCUGGGAAAAC-3′(SEQ ID NO: 2382) TTR-348 19 nt Target #2: 5′-CCAUUUGCCUCUGGGAAAA-3′(SEQ ID NO: 2766) TTR-348 19 nt Target #3: 5′-GCCAUUUGCCUCUGGGAAA-3′(SEQ ID NO: 3150) TTR-349 19 nt Target #1: 5′-AUUUGCCUCUGGGAAAACC-3′(SEQ ID NO: 2383) TTR-349 19 nt Target #2: 5′-CAUUUGCCUCUGGGAAAAC-3′(SEQ ID NO: 2767) TTR-349 19 nt Target #3: 5′-CCAUUUGCCUCUGGGAAAA-3′(SEQ ID NO: 3151) TTR-350 19 nt Target #1: 5′-UUUGCCUCUGGGAAAACCA-3′(SEQ ID NO: 2384) TTR-350 19 nt Target #2: 5′-AUUUGCCUCUGGGAAAACC-3′(SEQ ID NO: 2768) TTR-350 19 nt Target #3: 5′-CAUUUGCCUCUGGGAAAAC-3′(SEQ ID NO: 3152) TTR-351 19 nt Target #1: 5′-UUGCCUCUGGGAAAACCAG-3′(SEQ ID NO: 2385) TTR-351 19 nt Target #2: 5′-UUUGCCUCUGGGAAAACCA-3′(SEQ ID NO: 2769) TTR-351 19 nt Target #3: 5′-AUUUGCCUCUGGGAAAACC-3′(SEQ ID NO: 3153) TTR-352 19 nt Target #1: 5′-UGCCUCUGGGAAAACCAGU-3′(SEQ ID NO: 2386) TTR-352 19 nt Target #2: 5′-UUGCCUCUGGGAAAACCAG-3′(SEQ ID NO: 2770) TTR-352 19 nt Target #3: 5′-UUUGCCUCUGGGAAAACCA-3′(SEQ ID NO: 3154) TTR-353 19 nt Target #1: 5′-GCCUCUGGGAAAACCAGUG-3′(SEQ ID NO: 2387) TTR-353 19 nt Target #2: 5′-UGCCUCUGGGAAAACCAGU-3′(SEQ ID NO: 2771) TTR-353 19 nt Target #3: 5′-UUGCCUCUGGGAAAACCAG-3′(SEQ ID NO: 3155) TTR-354 19 nt Target #1: 5′-CCUCUGGGAAAACCAGUGA-3′(SEQ ID NO: 2388) TTR-354 19 nt Target #2: 5′-GCCUCUGGGAAAACCAGUG-3′(SEQ ID NO: 2772) TTR-354 19 nt Target #3: 5′-UGCCUCUGGGAAAACCAGU-3′(SEQ ID NO: 3156) TTR-355 19 nt Target #1: 5′-CUCUGGGAAAACCAGUGAG-3′(SEQ ID NO: 2389) TTR-355 19 nt Target #2: 5′-CCUCUGGGAAAACCAGUGA-3′(SEQ ID NO: 2773) TTR-355 19 nt Target #3: 5′-GCCUCUGGGAAAACCAGUG-3′(SEQ ID NO: 3157) TTR-356 19 nt Target #1: 5′-UCUGGGAAAACCAGUGAGU-3′(SEQ ID NO: 2390) TTR-356 19 nt Target #2: 5′-CUCUGGGAAAACCAGUGAG-3′(SEQ ID NO: 2774) TTR-356 19 nt Target #3: 5′-CCUCUGGGAAAACCAGUGA-3′(SEQ ID NO: 3158) TTR-357 19 nt Target #1: 5′-CUGGGAAAACCAGUGAGUC-3′(SEQ ID NO: 2391) TTR-357 19 nt Target #2: 5′-UCUGGGAAAACCAGUGAGU-3′(SEQ ID NO: 2775) TTR-357 19 nt Target #3: 5′-CUCUGGGAAAACCAGUGAG-3′(SEQ ID NO: 3159) TTR-358 19 nt Target #1: 5′-UGGGAAAACCAGUGAGUCU-3′(SEQ ID NO: 2392) TTR-358 19 nt Target #2: 5′-CUGGGAAAACCAGUGAGUC-3′(SEQ ID NO: 2776) TTR-358 19 nt Target #3: 5′-UCUGGGAAAACCAGUGAGU-3′(SEQ ID NO: 3160) TTR-359 19 nt Target #1: 5′-GGGAAAACCAGUGAGUCUG-3′(SEQ ID NO: 2393) TTR-359 19 nt Target #2: 5′-UGGGAAAACCAGUGAGUCU-3′(SEQ ID NO: 2777) TTR-359 19 nt Target #3: 5′-CUGGGAAAACCAGUGAGUC-3′(SEQ ID NO: 3161) TTR-360 19 nt Target #1: 5′-GGAAAACCAGUGAGUCUGG-3′(SEQ ID NO: 2394) TTR-360 19 nt Target #2: 5′-GGGAAAACCAGUGAGUCUG-3′(SEQ ID NO: 2778) TTR-360 19 nt Target #3: 5′-UGGGAAAACCAGUGAGUCU-3′(SEQ ID NO: 3162) TTR-361 19 nt Target #1: 5′-GAAAACCAGUGAGUCUGGA-3′(SEQ ID NO: 2395) TTR-361 19 nt Target #2: 5′-GGAAAACCAGUGAGUCUGG-3′(SEQ ID NO: 2779) TTR-361 19 nt Target #3: 5′-GGGAAAACCAGUGAGUCUG-3′(SEQ ID NO: 3163) TTR-381 19 nt Target #1: 5′-AGCUGCAUGGGCUCACAAC-3′(SEQ ID NO: 2396) TTR-381 19 nt Target #2: 5′-GAGCUGCAUGGGCUCACAA-3′(SEQ ID NO: 2780) TTR-381 19 nt Target #3: 5′-AGAGCUGCAUGGGCUCACA-3′(SEQ ID NO: 3164) TTR-382 19 nt Target #1: 5′-GCUGCAUGGGCUCACAACU-3′(SEQ ID NO: 2397) TTR-382 19 nt Target #2: 5′-AGCUGCAUGGGCUCACAAC-3′(SEQ ID NO: 2781) TTR-382 19 nt Target #3: 5′-GAGCUGCAUGGGCUCACAA-3′(SEQ ID NO: 3165) TTR-383 19 nt Target #1: 5′-CUGCAUGGGCUCACAACUG-3′(SEQ ID NO: 2398) TTR-383 19 nt Target #2: 5′-GCUGCAUGGGCUCACAACU-3′(SEQ ID NO: 2782) TTR-383 19 nt Target #3: 5′-AGCUGCAUGGGCUCACAAC-3′(SEQ ID NO: 3166) TTR-384 19 nt Target #1: 5′-UGCAUGGGCUCACAACUGA-3′(SEQ ID NO: 2399) TTR-384 19 nt Target #2: 5′-CUGCAUGGGCUCACAACUG-3′(SEQ ID NO: 2783) TTR-384 19 nt Target #3: 5′-GCUGCAUGGGCUCACAACU-3′(SEQ ID NO: 3167) TTR-385 19 nt Target #1: 5′-GCAUGGGCUCACAACUGAG-3′(SEQ ID NO: 2400) TTR-385 19 nt Target #2: 5′-UGCAUGGGCUCACAACUGA-3′(SEQ ID NO: 2784) TTR-385 19 nt Target #3: 5′-CUGCAUGGGCUCACAACUG-3′(SEQ ID NO: 3168) TTR-386 19 nt Target #1: 5′-CAUGGGCUCACAACUGAGG-3′(SEQ ID NO: 2401) TTR-386 19 nt Target #2: 5′-GCAUGGGCUCACAACUGAG-3′(SEQ ID NO: 2785) TTR-386 19 nt Target #3: 5′-UGCAUGGGCUCACAACUGA-3′(SEQ ID NO: 3169) TTR-387 19 nt Target #1: 5′-AUGGGCUCACAACUGAGGA-3′(SEQ ID NO: 2402) TTR-387 19 nt Target #2: 5′-CAUGGGCUCACAACUGAGG-3′(SEQ ID NO: 2786) TTR-387 19 nt Target #3: 5′-GCAUGGGCUCACAACUGAG-3′(SEQ ID NO: 3170) TTR-388 19 nt Target #1: 5′-UGGGCUCACAACUGAGGAG-3′(SEQ ID NO: 2403) TTR-388 19 nt Target #2: 5′-AUGGGCUCACAACUGAGGA-3′(SEQ ID NO: 2787) TTR-388 19 nt Target #3: 5′-CAUGGGCUCACAACUGAGG-3′(SEQ ID NO: 3171) TTR-389 19 nt Target #1: 5′-GGGCUCACAACUGAGGAGG-3′(SEQ ID NO: 2404) TTR-389 19 nt Target #2: 5′-UGGGCUCACAACUGAGGAG-3′(SEQ ID NO: 2788) TTR-389 19 nt Target #3: 5′-AUGGGCUCACAACUGAGGA-3′(SEQ ID NO: 3172) TTR-390 19 nt Target #1: 5′-GGCUCACAACUGAGGAGGA-3′(SEQ ID NO: 2405) TTR-390 19 nt Target #2: 5′-GGGCUCACAACUGAGGAGG-3′(SEQ ID NO: 2789) TTR-390 19 nt Target #3: 5′-UGGGCUCACAACUGAGGAG-3′(SEQ ID NO: 3173) TTR-391 19 nt Target #1: 5′-GCUCACAACUGAGGAGGAA-3′(SEQ ID NO: 2406) TTR-391 19 nt Target #2: 5′-GGCUCACAACUGAGGAGGA-3′(SEQ ID NO: 2790) TTR-391 19 nt Target #3: 5′-GGGCUCACAACUGAGGAGG-3′(SEQ ID NO: 3174) TTR-392 19 nt Target #1: 5′-CUCACAACUGAGGAGGAAU-3′(SEQ ID NO: 2407) TTR-392 19 nt Target #2: 5′-GCUCACAACUGAGGAGGAA-3′(SEQ ID NO: 2791) TTR-392 19 nt Target #3: 5′-GGCUCACAACUGAGGAGGA-3′(SEQ ID NO: 3175) TTR-393 19 nt Target #1: 5′-UCACAACUGAGGAGGAAUU-3′(SEQ ID NO: 2408) TTR-393 19 nt Target #2: 5′-CUCACAACUGAGGAGGAAU-3′(SEQ ID NO: 2792) TTR-393 19 nt Target #3: 5′-GCUCACAACUGAGGAGGAA-3′(SEQ ID NO: 3176) TTR-394 19 nt Target #1: 5′-CACAACUGAGGAGGAAUUU-3′(SEQ ID NO: 2409) TTR-394 19 nt Target #2: 5′-UCACAACUGAGGAGGAAUU-3′(SEQ ID NO: 2793) TTR-394 19 nt Target #3: 5′-CUCACAACUGAGGAGGAAU-3′(SEQ ID NO: 3177) TTR-395 19 nt Target #1: 5′-ACAACUGAGGAGGAAUUUG-3′(SEQ ID NO: 2410) TTR-395 19 nt Target #2: 5′-CACAACUGAGGAGGAAUUU-3′(SEQ ID NO: 2794) TTR-395 19 nt Target #3: 5′-UCACAACUGAGGAGGAAUU-3′(SEQ ID NO: 3178) TTR-396 19 nt Target #1: 5′-CAACUGAGGAGGAAUUUGU-3′(SEQ ID NO: 2411) TTR-396 19 nt Target #2: 5′-ACAACUGAGGAGGAAUUUG-3′(SEQ ID NO: 2795) TTR-396 19 nt Target #3: 5′-CACAACUGAGGAGGAAUUU-3′(SEQ ID NO: 3179) TTR-398 19 nt Target #1: 5′-ACUGAGGAGGAAUUUGUAG-3′(SEQ ID NO: 2412) TTR-398 19 nt Target #2: 5′-AACUGAGGAGGAAUUUGUA-3′(SEQ ID NO: 2796) TTR-398 19 nt Target #3: 5′-CAACUGAGGAGGAAUUUGU-3′(SEQ ID NO: 3180) TTR-399 19 nt Target #1: 5′-CUGAGGAGGAAUUUGUAGA-3′(SEQ ID NO: 2413) TTR-399 19 nt Target #2: 5′-ACUGAGGAGGAAUUUGUAG-3′(SEQ ID NO: 2797) TTR-399 19 nt Target #3: 5′-AACUGAGGAGGAAUUUGUA-3′(SEQ ID NO: 3181) TTR-400 19 nt Target #1: 5′-UGAGGAGGAAUUUGUAGAA-3′(SEQ ID NO: 2414) TTR-400 19 nt Target #2: 5′-CUGAGGAGGAAUUUGUAGA-3′(SEQ ID NO: 2798) TTR-400 19 nt Target #3: 5′-ACUGAGGAGGAAUUUGUAG-3′(SEQ ID NO: 3182) TTR-401 19 nt Target #1: 5′-GAGGAGGAAUUUGUAGAAG-3′(SEQ ID NO: 2415) TTR-401 19 nt Target #2: 5′-UGAGGAGGAAUUUGUAGAA-3′(SEQ ID NO: 2799) TTR-401 19 nt Target #3: 5′-CUGAGGAGGAAUUUGUAGA-3′(SEQ ID NO: 3183) TTR-402 19 nt Target #1: 5′-AGGAGGAAUUUGUAGAAGG-3′(SEQ ID NO: 2416) TTR-402 19 nt Target #2: 5′-GAGGAGGAAUUUGUAGAAG-3′(SEQ ID NO: 2800) TTR-402 19 nt Target #3: 5′-UGAGGAGGAAUUUGUAGAA-3′(SEQ ID NO: 3184) TTR-403 19 nt Target #1: 5′-GGAGGAAUUUGUAGAAGGG-3′(SEQ ID NO: 2417) TTR-403 19 nt Target #2: 5′-AGGAGGAAUUUGUAGAAGG-3′(SEQ ID NO: 2801) TTR-403 19 nt Target #3: 5′-GAGGAGGAAUUUGUAGAAG-3′(SEQ ID NO: 3185) TTR-404 19 nt Target #1: 5′-GAGGAAUUUGUAGAAGGGA-3′(SEQ ID NO: 2418) TTR-404 19 nt Target #2: 5′-GGAGGAAUUUGUAGAAGGG-3′(SEQ ID NO: 2802) TTR-404 19 nt Target #3: 5′-AGGAGGAAUUUGUAGAAGG-3′(SEQ ID NO: 3186) TTR-405 19 nt Target #1: 5′-AGGAAUUUGUAGAAGGGAU-3′(SEQ ID NO: 2419) TTR-405 19 nt Target #2: 5′-GAGGAAUUUGUAGAAGGGA-3′(SEQ ID NO: 2803) TTR-405 19 nt Target #3: 5′-GGAGGAAUUUGUAGAAGGG-3′(SEQ ID NO: 3187) TTR-406 19 nt Target #1: 5′-GGAAUUUGUAGAAGGGAUA-3′(SEQ ID NO: 2420) TTR-406 19 nt Target #2: 5′-AGGAAUUUGUAGAAGGGAU-3′(SEQ ID NO: 2804) TTR-406 19 nt Target #3: 5′-GAGGAAUUUGUAGAAGGGA-3′(SEQ ID NO: 3188) TTR-407 19 nt Target #1: 5′-GAAUUUGUAGAAGGGAUAU-3′(SEQ ID NO: 2421) TTR-407 19 nt Target #2: 5′-GGAAUUUGUAGAAGGGAUA-3′(SEQ ID NO: 2805) TTR-407 19 nt Target #3: 5′-AGGAAUUUGUAGAAGGGAU-3′(SEQ ID NO: 3189) TTR-408 19 nt Target #1: 5′-AAUUUGUAGAAGGGAUAUA-3′(SEQ ID NO: 2422) TTR-408 19 nt Target #2: 5′-GAAUUUGUAGAAGGGAUAU-3′(SEQ ID NO: 2806) TTR-408 19 nt Target #3: 5′-GGAAUUUGUAGAAGGGAUA-3′(SEQ ID NO: 3190) TTR-409 19 nt Target #1: 5′-AUUUGUAGAAGGGAUAUAC-3′(SEQ ID NO: 2423) TTR-409 19 nt Target #2: 5′-AAUUUGUAGAAGGGAUAUA-3′(SEQ ID NO: 2807) TTR-409 19 nt Target #3: 5′-GAAUUUGUAGAAGGGAUAU-3′(SEQ ID NO: 3191) TTR-410 19 nt Target #1: 5′-UUUGUAGAAGGGAUAUACA-3′(SEQ ID NO: 2424) TTR-410 19 nt Target #2: 5′-AUUUGUAGAAGGGAUAUAC-3′(SEQ ID NO: 2808) TTR-410 19 nt Target #3: 5′-AAUUUGUAGAAGGGAUAUA-3′(SEQ ID NO: 3192) TTR-411 19 nt Target #1: 5′-UUGUAGAAGGGAUAUACAA-3′(SEQ ID NO: 2425) TTR-411 19 nt Target #2: 5′-UUUGUAGAAGGGAUAUACA-3′(SEQ ID NO: 2809) TTR-411 19 nt Target #3: 5′-AUUUGUAGAAGGGAUAUAC-3′(SEQ ID NO: 3193) TTR-412 19 nt Target #1: 5′-UGUAGAAGGGAUAUACAAA-3′(SEQ ID NO: 2426) TTR-412 19 nt Target #2: 5′-UUGUAGAAGGGAUAUACAA-3′(SEQ ID NO: 2810) TTR-412 19 nt Target #3: 5′-UUUGUAGAAGGGAUAUACA-3′(SEQ ID NO: 3194) TTR-413 19 nt Target #1: 5′-GUAGAAGGGAUAUACAAAG-3′(SEQ ID NO: 2427) TTR-413 19 nt Target #2: 5′-UGUAGAAGGGAUAUACAAA-3′(SEQ ID NO: 2811) TTR-413 19 nt Target #3: 5′-UUGUAGAAGGGAUAUACAA-3′(SEQ ID NO: 3195) TTR-414 19 nt Target #1: 5′-UAGAAGGGAUAUACAAAGU-3′(SEQ ID NO: 2428) TTR-414 19 nt Target #2: 5′-GUAGAAGGGAUAUACAAAG-3′(SEQ ID NO: 2812) TTR-414 19 nt Target #3: 5′-UGUAGAAGGGAUAUACAAA-3′(SEQ ID NO: 3196) TTR-415 19 nt Target #1: 5′-AGAAGGGAUAUACAAAGUG-3′(SEQ ID NO: 2429) TTR-415 19 nt Target #2: 5′-UAGAAGGGAUAUACAAAGU-3′(SEQ ID NO: 2813) TTR-415 19 nt Target #3: 5′-GUAGAAGGGAUAUACAAAG-3′(SEQ ID NO: 3197) TTR-416 19 nt Target #1: 5′-GAAGGGAUAUACAAAGUGG-3′(SEQ ID NO: 2430) TTR-416 19 nt Target #2: 5′-AGAAGGGAUAUACAAAGUG-3′(SEQ ID NO: 2814) TTR-416 19 nt Target #3: 5′-UAGAAGGGAUAUACAAAGU-3′(SEQ ID NO: 3198) TTR-417 19 nt Target #1: 5′-AAGGGAUAUACAAAGUGGA-3′(SEQ ID NO: 2431) TTR-417 19 nt Target #2: 5′-GAAGGGAUAUACAAAGUGG-3′(SEQ ID NO: 2815) TTR-417 19 nt Target #3: 5′-AGAAGGGAUAUACAAAGUG-3′(SEQ ID NO: 3199) TTR-418 19 nt Target #1: 5′-AGGGAUAUACAAAGUGGAA-3′(SEQ ID NO: 2432) TTR-418 19 nt Target #2: 5′-AAGGGAUAUACAAAGUGGA-3′(SEQ ID NO: 2816) TTR-418 19 nt Target #3: 5′-GAAGGGAUAUACAAAGUGG-3′(SEQ ID NO: 3200) TTR-419 19 nt Target #1: 5′-GGGAUAUACAAAGUGGAAA-3′(SEQ ID NO: 2433) TTR-419 19 nt Target #2: 5′-AGGGAUAUACAAAGUGGAA-3′(SEQ ID NO: 2817) TTR-419 19 nt Target #3: 5′-AAGGGAUAUACAAAGUGGA-3′(SEQ ID NO: 3201) TTR-420 19 nt Target #1: 5′-GGAUAUACAAAGUGGAAAU-3′(SEQ ID NO: 2434) TTR-420 19 nt Target #2: 5′-GGGAUAUACAAAGUGGAAA-3′(SEQ ID NO: 2818) TTR-420 19 nt Target #3: 5′-AGGGAUAUACAAAGUGGAA-3′(SEQ ID NO: 3202) TTR-421 19 nt Target #1: 5′-GAUAUACAAAGUGGAAAUA-3′(SEQ ID NO: 2435) TTR-421 19 nt Target #2: 5′-GGAUAUACAAAGUGGAAAU-3′(SEQ ID NO: 2819) TTR-421 19 nt Target #3: 5′-GGGAUAUACAAAGUGGAAA-3′(SEQ ID NO: 3203) TTR-422 19 nt Target #1: 5′-AUAUACAAAGUGGAAAUAG-3′(SEQ ID NO: 2436) TTR-422 19 nt Target #2: 5′-GAUAUACAAAGUGGAAAUA-3′(SEQ ID NO: 2820) TTR-422 19 nt Target #3: 5′-GGAUAUACAAAGUGGAAAU-3′(SEQ ID NO: 3204) TTR-423 19 nt Target #1: 5′-UAUACAAAGUGGAAAUAGA-3′(SEQ ID NO: 2437) TTR-423 19 nt Target #2: 5′-AUAUACAAAGUGGAAAUAG-3′(SEQ ID NO: 2821) TTR-423 19 nt Target #3: 5′-GAUAUACAAAGUGGAAAUA-3′(SEQ ID NO: 3205) TTR-424 19 nt Target #1: 5′-AUACAAAGUGGAAAUAGAC-3′(SEQ ID NO: 2438) TTR-424 19 nt Target #2: 5′-UAUACAAAGUGGAAAUAGA-3′(SEQ ID NO: 2822) TTR-424 19 nt Target #3: 5′-AUAUACAAAGUGGAAAUAG-3′(SEQ ID NO: 3206) TTR-425 19 nt Target #1: 5′-UACAAAGUGGAAAUAGACA-3′(SEQ ID NO: 2439) TTR-425 19 nt Target #2: 5′-AUACAAAGUGGAAAUAGAC-3′(SEQ ID NO: 2823) TTR-425 19 nt Target #3: 5′-UAUACAAAGUGGAAAUAGA-3′(SEQ ID NO: 3207) TTR-426 19 nt Target #1: 5′-ACAAAGUGGAAAUAGACAC-3′(SEQ ID NO: 2440) TTR-426 19 nt Target #2: 5′-UACAAAGUGGAAAUAGACA-3′(SEQ ID NO: 2824) TTR-426 19 nt Target #3: 5′-AUACAAAGUGGAAAUAGAC-3′(SEQ ID NO: 3208) TTR-427 19 nt Target #1: 5′-CAAAGUGGAAAUAGACACC-3′(SEQ ID NO: 2441) TTR-427 19 nt Target #2: 5′-ACAAAGUGGAAAUAGACAC-3′(SEQ ID NO: 2825) TTR-427 19 nt Target #3: 5′-UACAAAGUGGAAAUAGACA-3′(SEQ ID NO: 3209) TTR-428 19 nt Target #1: 5′-AAAGUGGAAAUAGACACCA-3′(SEQ ID NO: 2442) TTR-428 19 nt Target #2: 5′-CAAAGUGGAAAUAGACACC-3′(SEQ ID NO: 2826) TTR-428 19 nt Target #3: 5′-ACAAAGUGGAAAUAGACAC-3′(SEQ ID NO: 3210) TTR-429 19 nt Target #1: 5′-AAGUGGAAAUAGACACCAA-3′(SEQ ID NO: 2443) TTR-429 19 nt Target #2: 5′-AAAGUGGAAAUAGACACCA-3′(SEQ ID NO: 2827) TTR-429 19 nt Target #3: 5′-CAAAGUGGAAAUAGACACC-3′(SEQ ID NO: 3211) TTR-430 19 nt Target #1: 5′-AGUGGAAAUAGACACCAAA-3′(SEQ ID NO: 2444) TTR-430 19 nt Target #2: 5′-AAGUGGAAAUAGACACCAA-3′(SEQ ID NO: 2828) TTR-430 19 nt Target #3: 5′-AAAGUGGAAAUAGACACCA-3′(SEQ ID NO: 3212) TTR-431 19 nt Target #1: 5′-GUGGAAAUAGACACCAAAU-3′(SEQ ID NO: 2445) TTR-431 19 nt Target #2: 5′-AGUGGAAAUAGACACCAAA-3′(SEQ ID NO: 2829) TTR-431 19 nt Target #3: 5′-AAGUGGAAAUAGACACCAA-3′(SEQ ID NO: 3213) TTR-432 19 nt Target #1: 5′-UGGAAAUAGACACCAAAUC-3′(SEQ ID NO: 2446) TTR-432 19 nt Target #2: 5′-GUGGAAAUAGACACCAAAU-3′(SEQ ID NO: 2830) TTR-432 19 nt Target #3: 5′-AGUGGAAAUAGACACCAAA-3′(SEQ ID NO: 3214) TTR-433 19 nt Target #1: 5′-GGAAAUAGACACCAAAUCU-3′(SEQ ID NO: 2447) TTR-433 19 nt Target #2: 5′-UGGAAAUAGACACCAAAUC-3′(SEQ ID NO: 2831) TTR-433 19 nt Target #3: 5′-GUGGAAAUAGACACCAAAU-3′(SEQ ID NO: 3215) TTR-434 19 nt Target #1: 5′-GAAAUAGACACCAAAUCUU-3′(SEQ ID NO: 2448) TTR-434 19 nt Target #2: 5′-GGAAAUAGACACCAAAUCU-3′(SEQ ID NO: 2832) TTR-434 19 nt Target #3: 5′-UGGAAAUAGACACCAAAUC-3′(SEQ ID NO: 3216) TTR-435 19 nt Target #1: 5′-AAAUAGACACCAAAUCUUA-3′(SEQ ID NO: 2449) TTR-435 19 nt Target #2: 5′-GAAAUAGACACCAAAUCUU-3′(SEQ ID NO: 2833) TTR-435 19 nt Target #3: 5′-GGAAAUAGACACCAAAUCU-3′(SEQ ID NO: 3217) TTR-436 19 nt Target #1: 5′-AAUAGACACCAAAUCUUAC-3′(SEQ ID NO: 2450) TTR-436 19 nt Target #2: 5′-AAAUAGACACCAAAUCUUA-3′(SEQ ID NO: 2834) TTR-436 19 nt Target #3: 5′-GAAAUAGACACCAAAUCUU-3′(SEQ ID NO: 3218) TTR-437 19 nt Target #1: 5′-AUAGACACCAAAUCUUACU-3′(SEQ ID NO: 2451) TTR-437 19 nt Target #2: 5′-AAUAGACACCAAAUCUUAC-3′(SEQ ID NO: 2835) TTR-437 19 nt Target #3: 5′-AAAUAGACACCAAAUCUUA-3′(SEQ ID NO: 3219) TTR-439 19 nt Target #1: 5′-AGACACCAAAUCUUACUGG-3′(SEQ ID NO: 2452) TTR-439 19 nt Target #2: 5′-UAGACACCAAAUCUUACUG-3′(SEQ ID NO: 2836) TTR-439 19 nt Target #3: 5′-AUAGACACCAAAUCUUACU-3′(SEQ ID NO: 3220) TTR-440 19 nt Target #1: 5′-GACACCAAAUCUUACUGGA-3′(SEQ ID NO: 2453) TTR-440 19 nt Target #2: 5′-AGACACCAAAUCUUACUGG-3′(SEQ ID NO: 2837) TTR-440 19 nt Target #3: 5′-UAGACACCAAAUCUUACUG-3′(SEQ ID NO: 3221) TTR-462 19 nt Target #1: 5′-CACUUGGCAUCUCCCCAUU-3′(SEQ ID NO: 2454) TTR-462 19 nt Target #2: 5′-GCACUUGGCAUCUCCCCAU-3′(SEQ ID NO: 2838) TTR-462 19 nt Target #3: 5′-GGCACUUGGCAUCUCCCCA-3′(SEQ ID NO: 3222) TTR-463 19 nt Target #1: 5′-ACUUGGCAUCUCCCCAUUC-3′(SEQ ID NO: 2455) TTR-463 19 nt Target #2: 5′-CACUUGGCAUCUCCCCAUU-3′(SEQ ID NO: 2839) TTR-463 19 nt Target #3: 5′-GCACUUGGCAUCUCCCCAU-3′(SEQ ID NO: 3223) TTR-464 19 nt Target #1: 5′-CUUGGCAUCUCCCCAUUCC-3′(SEQ ID NO: 2456) TTR-464 19 nt Target #2: 5′-ACUUGGCAUCUCCCCAUUC-3′(SEQ ID NO: 2840) TTR-464 19 nt Target #3: 5′-CACUUGGCAUCUCCCCAUU-3′(SEQ ID NO: 3224) TTR-465 19 nt Target #1: 5′-UUGGCAUCUCCCCAUUCCA-3′(SEQ ID NO: 2457) TTR-465 19 nt Target #2: 5′-CUUGGCAUCUCCCCAUUCC-3′(SEQ ID NO: 2841) TTR-465 19 nt Target #3: 5′-ACUUGGCAUCUCCCCAUUC-3′(SEQ ID NO: 3225) TTR-466 19 nt Target #1: 5′-UGGCAUCUCCCCAUUCCAU-3′(SEQ ID NO: 2458) TTR-466 19 nt Target #2: 5′-UUGGCAUCUCCCCAUUCCA-3′(SEQ ID NO: 2842) TTR-466 19 nt Target #3: 5′-CUUGGCAUCUCCCCAUUCC-3′(SEQ ID NO: 3226) TTR-467 19 nt Target #1: 5′-GGCAUCUCCCCAUUCCAUG-3′(SEQ ID NO: 2459) TTR-467 19 nt Target #2: 5′-UGGCAUCUCCCCAUUCCAU-3′(SEQ ID NO: 2843) TTR-467 19 nt Target #3: 5′-UUGGCAUCUCCCCAUUCCA-3′(SEQ ID NO: 3227) TTR-468 19 nt Target #1: 5′-GCAUCUCCCCAUUCCAUGA-3′(SEQ ID NO: 2460) TTR-468 19 nt Target #2: 5′-GGCAUCUCCCCAUUCCAUG-3′(SEQ ID NO: 2844) TTR-468 19 nt Target #3: 5′-UGGCAUCUCCCCAUUCCAU-3′(SEQ ID NO: 3228) TTR-469 19 nt Target #1: 5′-CAUCUCCCCAUUCCAUGAG-3′(SEQ ID NO: 2461) TTR-469 19 nt Target #2: 5′-GCAUCUCCCCAUUCCAUGA-3′(SEQ ID NO: 2845) TTR-469 19 nt Target #3: 5′-GGCAUCUCCCCAUUCCAUG-3′(SEQ ID NO: 3229) TTR-470 19 nt Target #1: 5′-AUCUCCCCAUUCCAUGAGC-3′(SEQ ID NO: 2462) TTR-470 19 nt Target #2: 5′-CAUCUCCCCAUUCCAUGAG-3′(SEQ ID NO: 2846) TTR-470 19 nt Target #3: 5′-GCAUCUCCCCAUUCCAUGA-3′(SEQ ID NO: 3230) TTR-471 19 nt Target #1: 5′-UCUCCCCAUUCCAUGAGCA-3′(SEQ ID NO: 2463) TTR-471 19 nt Target #2: 5′-AUCUCCCCAUUCCAUGAGC-3′(SEQ ID NO: 2847) TTR-471 19 nt Target #3: 5′-CAUCUCCCCAUUCCAUGAG-3′(SEQ ID NO: 3231) TTR-472 19 nt Target #1: 5′-CUCCCCAUUCCAUGAGCAU-3′(SEQ ID NO: 2464) TTR-472 19 nt Target #2: 5′-UCUCCCCAUUCCAUGAGCA-3′(SEQ ID NO: 2848) TTR-472 19 nt Target #3: 5′-AUCUCCCCAUUCCAUGAGC-3′(SEQ ID NO: 3232) TTR-473 19 nt Target #1: 5′-UCCCCAUUCCAUGAGCAUG-3′(SEQ ID NO: 2465) TTR-473 19 nt Target #2: 5′-CUCCCCAUUCCAUGAGCAU-3′(SEQ ID NO: 2849) TTR-473 19 nt Target #3: 5′-UCUCCCCAUUCCAUGAGCA-3′(SEQ ID NO: 3233) TTR-474 19 nt Target #1: 5′-CCCCAUUCCAUGAGCAUGC-3′(SEQ ID NO: 2466) TTR-474 19 nt Target #2: 5′-UCCCCAUUCCAUGAGCAUG-3′(SEQ ID NO: 2850) TTR-474 19 nt Target #3: 5′-CUCCCCAUUCCAUGAGCAU-3′(SEQ ID NO: 3234) TTR-482 19 nt Target #1: 5′-CAUGAGCAUGCAGAGGUGG-3′(SEQ ID NO: 2467) TTR-482 19 nt Target #2: 5′-CCAUGAGCAUGCAGAGGUG-3′(SEQ ID NO: 2851) TTR-482 19 nt Target #3: 5′-UCCAUGAGCAUGCAGAGGU-3′(SEQ ID NO: 3235) TTR-483 19 nt Target #1: 5′-AUGAGCAUGCAGAGGUGGU-3′(SEQ ID NO: 2468) TTR-483 19 nt Target #2: 5′-CAUGAGCAUGCAGAGGUGG-3′(SEQ ID NO: 2852) TTR-483 19 nt Target #3: 5′-CCAUGAGCAUGCAGAGGUG-3′(SEQ ID NO: 3236) TTR-484 19 nt Target #1: 5′-UGAGCAUGCAGAGGUGGUA-3′(SEQ ID NO: 2469) TTR-484 19 nt Target #2: 5′-AUGAGCAUGCAGAGGUGGU-3′(SEQ ID NO: 2853) TTR-484 19 nt Target #3: 5′-CAUGAGCAUGCAGAGGUGG-3′(SEQ ID NO: 3237) TTR-485 19 nt Target #1: 5′-GAGCAUGCAGAGGUGGUAU-3′(SEQ ID NO: 2470) TTR-485 19 nt Target #2: 5′-UGAGCAUGCAGAGGUGGUA-3′(SEQ ID NO: 2854) TTR-485 19 nt Target #3: 5′-AUGAGCAUGCAGAGGUGGU-3′(SEQ ID NO: 3238) TTR-489 19 nt Target #1: 5′-AUGCAGAGGUGGUAUUCAC-3′(SEQ ID NO: 2471) TTR-489 19 nt Target #2: 5′-CAUGCAGAGGUGGUAUUCA-3′(SEQ ID NO: 2855) TTR-489 19 nt Target #3: 5′-GCAUGCAGAGGUGGUAUUC-3′(SEQ ID NO: 3239) TTR-493 19 nt Target #1: 5′-AGAGGUGGUAUUCACAGCC-3′(SEQ ID NO: 2472) TTR-493 19 nt Target #2: 5′-CAGAGGUGGUAUUCACAGC-3′(SEQ ID NO: 2856) TTR-493 19 nt Target #3: 5′-GCAGAGGUGGUAUUCACAG-3′(SEQ ID NO: 3240) TTR-494 19 nt Target #1: 5′-GAGGUGGUAUUCACAGCCA-3′(SEQ ID NO: 2473) TTR-494 19 nt Target #2: 5′-AGAGGUGGUAUUCACAGCC-3′(SEQ ID NO: 2857) TTR-494 19 nt Target #3: 5′-CAGAGGUGGUAUUCACAGC-3′(SEQ ID NO: 3241) TTR-581 19 nt Target #1: 5′-GUCGUCACCAAUCCCAAGG-3′(SEQ ID NO: 2474) TTR-581 19 nt Target #2: 5′-UGUCGUCACCAAUCCCAAG-3′(SEQ ID NO: 2858) TTR-581 19 nt Target #3: 5′-CUGUCGUCACCAAUCCCAA-3′(SEQ ID NO: 3242) TTR-631 19 nt Target #1: 5′-GGACGAGGGAUGGGAUUUC-3′(SEQ ID NO: 2475) TTR-631 19 nt Target #2: 5′-AGGACGAGGGAUGGGAUUU-3′(SEQ ID NO: 2859) TTR-631 19 nt Target #3: 5′-AAGGACGAGGGAUGGGAUU-3′(SEQ ID NO: 3243) TTR-632 19 nt Target #1: 5′-GACGAGGGAUGGGAUUUCA-3′(SEQ ID NO: 2476) TTR-632 19 nt Target #2: 5′-GGACGAGGGAUGGGAUUUC-3′(SEQ ID NO: 2860) TTR-632 19 nt Target #3: 5′-AGGACGAGGGAUGGGAUUU-3′(SEQ ID NO: 3244) TTR-635 19 nt Target #1: 5′-GAGGGAUGGGAUUUCAUGU-3′(SEQ ID NO: 2477) TTR-635 19 nt Target #2: 5′-CGAGGGAUGGGAUUUCAUG-3′(SEQ ID NO: 2861) TTR-635 19 nt Target #3: 5′-ACGAGGGAUGGGAUUUCAU-3′(SEQ ID NO: 3245) TTR-636 19 nt Target #1: 5′-AGGGAUGGGAUUUCAUGUA-3′(SEQ ID NO: 2478) TTR-636 19 nt Target #2: 5′-GAGGGAUGGGAUUUCAUGU-3′(SEQ ID NO: 2862) TTR-636 19 nt Target #3: 5′-CGAGGGAUGGGAUUUCAUG-3′(SEQ ID NO: 3246) TTR-637 19 nt Target #1: 5′-GGGAUGGGAUUUCAUGUAA-3′(SEQ ID NO: 2479) TTR-637 19 nt Target #2: 5′-AGGGAUGGGAUUUCAUGUA-3′(SEQ ID NO: 2863) TTR-637 19 nt Target #3: 5′-GAGGGAUGGGAUUUCAUGU-3′(SEQ ID NO: 3247) TTR-639 19 nt Target #1: 5′-GAUGGGAUUUCAUGUAACC-3′(SEQ ID NO: 2480) TTR-639 19 nt Target #2: 5′-GGAUGGGAUUUCAUGUAAC-3′(SEQ ID NO: 2864) TTR-639 19 nt Target #3: 5′-GGGAUGGGAUUUCAUGUAA-3′(SEQ ID NO: 3248) TTR-640 19 nt Target #1: 5′-AUGGGAUUUCAUGUAACCA-3′(SEQ ID NO: 2481) TTR-640 19 nt Target #2: 5′-GAUGGGAUUUCAUGUAACC-3′(SEQ ID NO: 2865) TTR-640 19 nt Target #3: 5′-GGAUGGGAUUUCAUGUAAC-3′(SEQ ID NO: 3249) TTR-641 19 nt Target #1: 5′-UGGGAUUUCAUGUAACCAA-3′(SEQ ID NO: 2482) TTR-641 19 nt Target #2: 5′-AUGGGAUUUCAUGUAACCA-3′(SEQ ID NO: 2866) TTR-641 19 nt Target #3: 5′-GAUGGGAUUUCAUGUAACC-3′(SEQ ID NO: 3250) TTR-642 19 nt Target #1: 5′-GGGAUUUCAUGUAACCAAG-3′(SEQ ID NO: 2483) TTR-642 19 nt Target #2: 5′-UGGGAUUUCAUGUAACCAA-3′(SEQ ID NO: 2867) TTR-642 19 nt Target #3: 5′-AUGGGAUUUCAUGUAACCA-3′(SEQ ID NO: 3251) TTR-643 19 nt Target #1: 5′-GGAUUUCAUGUAACCAAGA-3′(SEQ ID NO: 2484) TTR-643 19 nt Target #2: 5′-GGGAUUUCAUGUAACCAAG-3′(SEQ ID NO: 2868) TTR-643 19 nt Target #3: 5′-UGGGAUUUCAUGUAACCAA-3′(SEQ ID NO: 3252) TTR-644 19 nt Target #1: 5′-GAUUUCAUGUAACCAAGAG-3′(SEQ ID NO: 2485) TTR-644 19 nt Target #2: 5′-GGAUUUCAUGUAACCAAGA-3′(SEQ ID NO: 2869) TTR-644 19 nt Target #3: 5′-GGGAUUUCAUGUAACCAAG-3′(SEQ ID NO: 3253) TTR-645 19 nt Target #1: 5′-AUUUCAUGUAACCAAGAGU-3′(SEQ ID NO: 2486) TTR-645 19 nt Target #2: 5′-GAUUUCAUGUAACCAAGAG-3′(SEQ ID NO: 2870) TTR-645 19 nt Target #3: 5′-GGAUUUCAUGUAACCAAGA-3′(SEQ ID NO: 3254) TTR-646 19 nt Target #1: 5′-UUUCAUGUAACCAAGAGUA-3′(SEQ ID NO: 2487) TTR-646 19 nt Target #2: 5′-AUUUCAUGUAACCAAGAGU-3′(SEQ ID NO: 2871) TTR-646 19 nt Target #3: 5′-GAUUUCAUGUAACCAAGAG-3′(SEQ ID NO: 3255) TTR-647 19 nt Target #1: 5′-UUCAUGUAACCAAGAGUAU-3′(SEQ ID NO: 2488) TTR-647 19 nt Target #2: 5′-UUUCAUGUAACCAAGAGUA-3′(SEQ ID NO: 2872) TTR-647 19 nt Target #3: 5′-AUUUCAUGUAACCAAGAGU-3′(SEQ ID NO: 3256) TTR-648 19 nt Target #1: 5′-UCAUGUAACCAAGAGUAUU-3′(SEQ ID NO: 2489) TTR-648 19 nt Target #2: 5′-UUCAUGUAACCAAGAGUAU-3′(SEQ ID NO: 2873) TTR-648 19 nt Target #3: 5′-UUUCAUGUAACCAAGAGUA-3′(SEQ ID NO: 3257) TTR-649 19 nt Target #1: 5′-CAUGUAACCAAGAGUAUUC-3′(SEQ ID NO: 2490) TTR-649 19 nt Target #2: 5′-UCAUGUAACCAAGAGUAUU-3′(SEQ ID NO: 2874) TTR-649 19 nt Target #3: 5′-UUCAUGUAACCAAGAGUAU-3′(SEQ ID NO: 3258) TTR-650 19 nt Target #1: 5′-AUGUAACCAAGAGUAUUCC-3′(SEQ ID NO: 2491) TTR-650 19 nt Target #2: 5′-CAUGUAACCAAGAGUAUUC-3′(SEQ ID NO: 2875) TTR-650 19 nt Target #3: 5′-UCAUGUAACCAAGAGUAUU-3′(SEQ ID NO: 3259) TTR-651 19 nt Target #1: 5′-UGUAACCAAGAGUAUUCCA-3′(SEQ ID NO: 2492) TTR-651 19 nt Target #2: 5′-AUGUAACCAAGAGUAUUCC-3′(SEQ ID NO: 2876) TTR-651 19 nt Target #3: 5′-CAUGUAACCAAGAGUAUUC-3′(SEQ ID NO: 3260) TTR-652 19 nt Target #1: 5′-GUAACCAAGAGUAUUCCAU-3′(SEQ ID NO: 2493) TTR-652 19 nt Target #2: 5′-UGUAACCAAGAGUAUUCCA-3′(SEQ ID NO: 2877) TTR-652 19 nt Target #3: 5′-AUGUAACCAAGAGUAUUCC-3′(SEQ ID NO: 3261) TTR-653 19 nt Target #1: 5′-UAACCAAGAGUAUUCCAUU-3′(SEQ ID NO: 2494) TTR-653 19 nt Target #2: 5′-GUAACCAAGAGUAUUCCAU-3′(SEQ ID NO: 2878) TTR-653 19 nt Target #3: 5′-UGUAACCAAGAGUAUUCCA-3′(SEQ ID NO: 3262) TTR-654 19 nt Target #1: 5′-AACCAAGAGUAUUCCAUUU-3′(SEQ ID NO: 2495) TTR-654 19 nt Target #2: 5′-UAACCAAGAGUAUUCCAUU-3′(SEQ ID NO: 2879) TTR-654 19 nt Target #3: 5′-GUAACCAAGAGUAUUCCAU-3′(SEQ ID NO: 3263) TTR-655 19 nt Target #1: 5′-ACCAAGAGUAUUCCAUUUU-3′(SEQ ID NO: 2496) TTR-655 19 nt Target #2: 5′-AACCAAGAGUAUUCCAUUU-3′(SEQ ID NO: 2880) TTR-655 19 nt Target #3: 5′-UAACCAAGAGUAUUCCAUU-3′(SEQ ID NO: 3264) TTR-656 19 nt Target #1: 5′-CCAAGAGUAUUCCAUUUUU-3′(SEQ ID NO: 2497) TTR-656 19 nt Target #2: 5′-ACCAAGAGUAUUCCAUUUU-3′(SEQ ID NO: 2881) TTR-656 19 nt Target #3: 5′-AACCAAGAGUAUUCCAUUU-3′(SEQ ID NO: 3265) TTR-657 19 nt Target #1: 5′-CAAGAGUAUUCCAUUUUUA-3′(SEQ ID NO: 2498) TTR-657 19 nt Target #2: 5′-CCAAGAGUAUUCCAUUUUU-3′(SEQ ID NO: 2882) TTR-657 19 nt Target #3: 5′-ACCAAGAGUAUUCCAUUUU-3′(SEQ ID NO: 3266) TTR-658 19 nt Target #1: 5′-AAGAGUAUUCCAUUUUUAC-3′(SEQ ID NO: 2499) TTR-658 19 nt Target #2: 5′-CAAGAGUAUUCCAUUUUUA-3′(SEQ ID NO: 2883) TTR-658 19 nt Target #3: 5′-CCAAGAGUAUUCCAUUUUU-3′(SEQ ID NO: 3267) TTR-659 19 nt Target #1: 5′-AGAGUAUUCCAUUUUUACU-3′(SEQ ID NO: 2500) TTR-659 19 nt Target #2: 5′-AAGAGUAUUCCAUUUUUAC-3′(SEQ ID NO: 2884) TTR-659 19 nt Target #3: 5′-CAAGAGUAUUCCAUUUUUA-3′(SEQ ID NO: 3268) TTR-660 19 nt Target #1: 5′-GAGUAUUCCAUUUUUACUA-3′(SEQ ID NO: 2501) TTR-660 19 nt Target #2: 5′-AGAGUAUUCCAUUUUUACU-3′(SEQ ID NO: 2885) TTR-660 19 nt Target #3: 5′-AAGAGUAUUCCAUUUUUAC-3′(SEQ ID NO: 3269) TTR-661 19 nt Target #1: 5′-AGUAUUCCAUUUUUACUAA-3′(SEQ ID NO: 2502) TTR-661 19 nt Target #2: 5′-GAGUAUUCCAUUUUUACUA-3′(SEQ ID NO: 2886) TTR-661 19 nt Target #3: 5′-AGAGUAUUCCAUUUUUACU-3′(SEQ ID NO: 3270) TTR-662 19 nt Target #1: 5′-GUAUUCCAUUUUUACUAAA-3′(SEQ ID NO: 2503) TTR-662 19 nt Target #2: 5′-AGUAUUCCAUUUUUACUAA-3′(SEQ ID NO: 2887) TTR-662 19 nt Target #3: 5′-GAGUAUUCCAUUUUUACUA-3′(SEQ ID NO: 3271) TTR-663 19 nt Target #1: 5′-UAUUCCAUUUUUACUAAAG-3′(SEQ ID NO: 2504) TTR-663 19 nt Target #2: 5′-GUAUUCCAUUUUUACUAAA-3′(SEQ ID NO: 2888) TTR-663 19 nt Target #3: 5′-AGUAUUCCAUUUUUACUAA-3′(SEQ ID NO: 3272) TTR-664 19 nt Target #1: 5′-AUUCCAUUUUUACUAAAGC-3′(SEQ ID NO: 2505) TTR-664 19 nt Target #2: 5′-UAUUCCAUUUUUACUAAAG-3′(SEQ ID NO: 2889) TTR-664 19 nt Target #3: 5′-GUAUUCCAUUUUUACUAAA-3′(SEQ ID NO: 3273) TTR-665 19 nt Target #1: 5′-UUCCAUUUUUACUAAAGCA-3′(SEQ ID NO: 2506) TTR-665 19 nt Target #2: 5′-AUUCCAUUUUUACUAAAGC-3′(SEQ ID NO: 2890) TTR-665 19 nt Target #3: 5′-UAUUCCAUUUUUACUAAAG-3′(SEQ ID NO: 3274) TTR-666 19 nt Target #1: 5′-UCCAUUUUUACUAAAGCAG-3′(SEQ ID NO: 2507) TTR-666 19 nt Target #2: 5′-UUCCAUUUUUACUAAAGCA-3′(SEQ ID NO: 2891) TTR-666 19 nt Target #3: 5′-AUUCCAUUUUUACUAAAGC-3′(SEQ ID NO: 3275) TTR-667 19 nt Target #1: 5′-CCAUUUUUACUAAAGCAGU-3′(SEQ ID NO: 2508) TTR-667 19 nt Target #2: 5′-UCCAUUUUUACUAAAGCAG-3′(SEQ ID NO: 2892) TTR-667 19 nt Target #3: 5′-UUCCAUUUUUACUAAAGCA-3′(SEQ ID NO: 3276) TTR-668 19 nt Target #1: 5′-CAUUUUUACUAAAGCAGUG-3′(SEQ ID NO: 2509) TTR-668 19 nt Target #2: 5′-CCAUUUUUACUAAAGCAGU-3′(SEQ ID NO: 2893) TTR-668 19 nt Target #3: 5′-UCCAUUUUUACUAAAGCAG-3′(SEQ ID NO: 3277) TTR-669 19 nt Target #1: 5′-AUUUUUACUAAAGCAGUGU-3′(SEQ ID NO: 2510) TTR-669 19 nt Target #2: 5′-CAUUUUUACUAAAGCAGUG-3′(SEQ ID NO: 2894) TTR-669 19 nt Target #3: 5′-CCAUUUUUACUAAAGCAGU-3′(SEQ ID NO: 3278) TTR-670 19 nt Target #1: 5′-UUUUUACUAAAGCAGUGUU-3′(SEQ ID NO: 2511) TTR-670 19 nt Target #2: 5′-AUUUUUACUAAAGCAGUGU-3′(SEQ ID NO: 2895) TTR-670 19 nt Target #3: 5′-CAUUUUUACUAAAGCAGUG-3′(SEQ ID NO: 3279) TTR-671 19 nt Target #1: 5′-UUUUACUAAAGCAGUGUUU-3′(SEQ ID NO: 2512) TTR-671 19 nt Target #2: 5′-UUUUUACUAAAGCAGUGUU-3′(SEQ ID NO: 2896) TTR-671 19 nt Target #3: 5′-AUUUUUACUAAAGCAGUGU-3′(SEQ ID NO: 3280) TTR-672 19 nt Target #1: 5′-UUUACUAAAGCAGUGUUUU-3′(SEQ ID NO: 2513) TTR-672 19 nt Target #2: 5′-UUUUACUAAAGCAGUGUUU-3′(SEQ ID NO: 2897) TTR-672 19 nt Target #3: 5′-UUUUUACUAAAGCAGUGUU-3′(SEQ ID NO: 3281) TTR-673 19 nt Target #1: 5′-UUACUAAAGCAGUGUUUUC-3′(SEQ ID NO: 2514) TTR-673 19 nt Target #2: 5′-UUUACUAAAGCAGUGUUUU-3′(SEQ ID NO: 2898) TTR-673 19 nt Target #3: 5′-UUUUACUAAAGCAGUGUUU-3′(SEQ ID NO: 3282) TTR-674 19 nt Target #1: 5′-UACUAAAGCAGUGUUUUCA-3′(SEQ ID NO: 2515) TTR-674 19 nt Target #2: 5′-UUACUAAAGCAGUGUUUUC-3′(SEQ ID NO: 2899) TTR-674 19 nt Target #3: 5′-UUUACUAAAGCAGUGUUUU-3′(SEQ ID NO: 3283) TTR-675 19 nt Target #1: 5′-ACUAAAGCAGUGUUUUCAC-3′(SEQ ID NO: 2516) TTR-675 19 nt Target #2: 5′-UACUAAAGCAGUGUUUUCA-3′(SEQ ID NO: 2900) TTR-675 19 nt Target #3: 5′-UUACUAAAGCAGUGUUUUC-3′(SEQ ID NO: 3284) TTR-676 19 nt Target #1: 5′-CUAAAGCAGUGUUUUCACC-3′(SEQ ID NO: 2517) TTR-676 19 nt Target #2: 5′-ACUAAAGCAGUGUUUUCAC-3′(SEQ ID NO: 2901) TTR-676 19 nt Target #3: 5′-UACUAAAGCAGUGUUUUCA-3′(SEQ ID NO: 3285) TTR-677 19 nt Target #1: 5′-UAAAGCAGUGUUUUCACCU-3′(SEQ ID NO: 2518) TTR-677 19 nt Target #2: 5′-CUAAAGCAGUGUUUUCACC-3′(SEQ ID NO: 2902) TTR-677 19 nt Target #3: 5′-ACUAAAGCAGUGUUUUCAC-3′(SEQ ID NO: 3286) TTR-678 19 nt Target #1: 5′-AAAGCAGUGUUUUCACCUC-3′(SEQ ID NO: 2519) TTR-678 19 nt Target #2: 5′-UAAAGCAGUGUUUUCACCU-3′(SEQ ID NO: 2903) TTR-678 19 nt Target #3: 5′-CUAAAGCAGUGUUUUCACC-3′(SEQ ID NO: 3287) TTR-679 19 nt Target #1: 5′-AAGCAGUGUUUUCACCUCA-3′(SEQ ID NO: 2520) TTR-679 19 nt Target #2: 5′-AAAGCAGUGUUUUCACCUC-3′(SEQ ID NO: 2904) TTR-679 19 nt Target #3: 5′-UAAAGCAGUGUUUUCACCU-3′(SEQ ID NO: 3288) TTR-680 19 nt Target #1: 5′-AGCAGUGUUUUCACCUCAU-3′(SEQ ID NO: 2521) TTR-680 19 nt Target #2: 5′-AAGCAGUGUUUUCACCUCA-3′(SEQ ID NO: 2905) TTR-680 19 nt Target #3: 5′-AAAGCAGUGUUUUCACCUC-3′(SEQ ID NO: 3289) TTR-681 19 nt Target #1: 5′-GCAGUGUUUUCACCUCAUA-3′(SEQ ID NO: 2522) TTR-681 19 nt Target #2: 5′-AGCAGUGUUUUCACCUCAU-3′(SEQ ID NO: 2906) TTR-681 19 nt Target #3: 5′-AAGCAGUGUUUUCACCUCA-3′(SEQ ID NO: 3290) TTR-682 19 nt Target #1: 5′-CAGUGUUUUCACCUCAUAU-3′(SEQ ID NO: 2523) TTR-682 19 nt Target #2: 5′-GCAGUGUUUUCACCUCAUA-3′(SEQ ID NO: 2907) TTR-682 19 nt Target #3: 5′-AGCAGUGUUUUCACCUCAU-3′(SEQ ID NO: 3291) TTR-683 19 nt Target #1: 5′-AGUGUUUUCACCUCAUAUG-3′(SEQ ID NO: 2524) TTR-683 19 nt Target #2: 5′-CAGUGUUUUCACCUCAUAU-3′(SEQ ID NO: 2908) TTR-683 19 nt Target #3: 5′-GCAGUGUUUUCACCUCAUA-3′(SEQ ID NO: 3292) TTR-684 19 nt Target #1: 5′-GUGUUUUCACCUCAUAUGC-3′(SEQ ID NO: 2525) TTR-684 19 nt Target #2: 5′-AGUGUUUUCACCUCAUAUG-3′(SEQ ID NO: 2909) TTR-684 19 nt Target #3: 5′-CAGUGUUUUCACCUCAUAU-3′(SEQ ID NO: 3293) TTR-685 19 nt Target #1: 5′-UGUUUUCACCUCAUAUGCU-3′(SEQ ID NO: 2526) TTR-685 19 nt Target #2: 5′-GUGUUUUCACCUCAUAUGC-3′(SEQ ID NO: 2910) TTR-685 19 nt Target #3: 5′-AGUGUUUUCACCUCAUAUG-3′(SEQ ID NO: 3294) TTR-686 19 nt Target #1: 5′-GUUUUCACCUCAUAUGCUA-3′(SEQ ID NO: 2527) TTR-686 19 nt Target #2: 5′-UGUUUUCACCUCAUAUGCU-3′(SEQ ID NO: 2911) TTR-686 19 nt Target #3: 5′-GUGUUUUCACCUCAUAUGC-3′(SEQ ID NO: 3295) TTR-687 19 nt Target #1: 5′-UUUUCACCUCAUAUGCUAU-3′(SEQ ID NO: 2528) TTR-687 19 nt Target #2: 5′-GUUUUCACCUCAUAUGCUA-3′(SEQ ID NO: 2912) TTR-687 19 nt Target #3: 5′-UGUUUUCACCUCAUAUGCU-3′(SEQ ID NO: 3296) TTR-688 19 nt Target #1: 5′-UUUCACCUCAUAUGCUAUG-3′(SEQ ID NO: 2529) TTR-688 19 nt Target #2: 5′-UUUUCACCUCAUAUGCUAU-3′(SEQ ID NO: 2913) TTR-688 19 nt Target #3: 5′-GUUUUCACCUCAUAUGCUA-3′(SEQ ID NO: 3297) TTR-689 19 nt Target #1: 5′-UUCACCUCAUAUGCUAUGU-3′(SEQ ID NO: 2530) TTR-689 19 nt Target #2: 5′-UUUCACCUCAUAUGCUAUG-3′(SEQ ID NO: 2914) TTR-689 19 nt Target #3: 5′-UUUUCACCUCAUAUGCUAU-3′(SEQ ID NO: 3298) TTR-690 19 nt Target #1: 5′-UCACCUCAUAUGCUAUGUU-3′(SEQ ID NO: 2531) TTR-690 19 nt Target #2: 5′-UUCACCUCAUAUGCUAUGU-3′(SEQ ID NO: 2915) TTR-690 19 nt Target #3: 5′-UUUCACCUCAUAUGCUAUG-3′(SEQ ID NO: 3299) TTR-691 19 nt Target #1: 5′-CACCUCAUAUGCUAUGUUA-3′(SEQ ID NO: 2532) TTR-691 19 nt Target #2: 5′-UCACCUCAUAUGCUAUGUU-3′(SEQ ID NO: 2916) TTR-691 19 nt Target #3: 5′-UUCACCUCAUAUGCUAUGU-3′(SEQ ID NO: 3300) TTR-692 19 nt Target #1: 5′-ACCUCAUAUGCUAUGUUAG-3′(SEQ ID NO: 2533) TTR-692 19 nt Target #2: 5′-CACCUCAUAUGCUAUGUUA-3′(SEQ ID NO: 2917) TTR-692 19 nt Target #3: 5′-UCACCUCAUAUGCUAUGUU-3′(SEQ ID NO: 3301) TTR-693 19 nt Target #1: 5′-CCUCAUAUGCUAUGUUAGA-3′(SEQ ID NO: 2534) TTR-693 19 nt Target #2: 5′-ACCUCAUAUGCUAUGUUAG-3′(SEQ ID NO: 2918) TTR-693 19 nt Target #3: 5′-CACCUCAUAUGCUAUGUUA-3′(SEQ ID NO: 3302) TTR-694 19 nt Target #1: 5′-CUCAUAUGCUAUGUUAGAA-3′(SEQ ID NO: 2535) TTR-694 19 nt Target #2: 5′-CCUCAUAUGCUAUGUUAGA-3′(SEQ ID NO: 2919) TTR-694 19 nt Target #3: 5′-ACCUCAUAUGCUAUGUUAG-3′(SEQ ID NO: 3303) TTR-695 19 nt Target #1: 5′-UCAUAUGCUAUGUUAGAAG-3′(SEQ ID NO: 2536) TTR-695 19 nt Target #2: 5′-CUCAUAUGCUAUGUUAGAA-3′(SEQ ID NO: 2920) TTR-695 19 nt Target #3: 5′-CCUCAUAUGCUAUGUUAGA-3′(SEQ ID NO: 3304) TTR-696 19 nt Target #1: 5′-CAUAUGCUAUGUUAGAAGU-3′(SEQ ID NO: 2537) TTR-696 19 nt Target #2: 5′-UCAUAUGCUAUGUUAGAAG-3′(SEQ ID NO: 2921) TTR-696 19 nt Target #3: 5′-CUCAUAUGCUAUGUUAGAA-3′(SEQ ID NO: 3305) TTR-697 19 nt Target #1: 5′-AUAUGCUAUGUUAGAAGUC-3′(SEQ ID NO: 2538) TTR-697 19 nt Target #2: 5′-CAUAUGCUAUGUUAGAAGU-3′(SEQ ID NO: 2922) TTR-697 19 nt Target #3: 5′-UCAUAUGCUAUGUUAGAAG-3′(SEQ ID NO: 3306) TTR-698 19 nt Target #1: 5′-UAUGCUAUGUUAGAAGUCC-3′(SEQ ID NO: 2539) TTR-698 19 nt Target #2: 5′-AUAUGCUAUGUUAGAAGUC-3′(SEQ ID NO: 2923) TTR-698 19 nt Target #3: 5′-CAUAUGCUAUGUUAGAAGU-3′(SEQ ID NO: 3307) TTR-699 19 nt Target #1: 5′-AUGCUAUGUUAGAAGUCCA-3′(SEQ ID NO: 2540) TTR-699 19 nt Target #2: 5′-UAUGCUAUGUUAGAAGUCC-3′(SEQ ID NO: 2924) TTR-699 19 nt Target #3: 5′-AUAUGCUAUGUUAGAAGUC-3′(SEQ ID NO: 3308) TTR-702 19 nt Target #1: 5′-CUAUGUUAGAAGUCCAGGC-3′(SEQ ID NO: 2541) TTR-702 19 nt Target #2: 5′-GCUAUGUUAGAAGUCCAGG-3′(SEQ ID NO: 2925) TTR-702 19 nt Target #3: 5′-UGCUAUGUUAGAAGUCCAG-3′(SEQ ID NO: 3309) TTR-704 19 nt Target #1: 5′-AUGUUAGAAGUCCAGGCAG-3′(SEQ ID NO: 2542) TTR-704 19 nt Target #2: 5′-UAUGUUAGAAGUCCAGGCA-3′(SEQ ID NO: 2926) TTR-704 19 nt Target #3: 5′-CUAUGUUAGAAGUCCAGGC-3′(SEQ ID NO: 3310) TTR-705 19 nt Target #1: 5′-UGUUAGAAGUCCAGGCAGA-3′(SEQ ID NO: 2543) TTR-705 19 nt Target #2: 5′-AUGUUAGAAGUCCAGGCAG-3′(SEQ ID NO: 2927) TTR-705 19 nt Target #3: 5′-UAUGUUAGAAGUCCAGGCA-3′(SEQ ID NO: 3311) TTR-706 19 nt Target #1: 5′-GUUAGAAGUCCAGGCAGAG-3′(SEQ ID NO: 2544) TTR-706 19 nt Target #2: 5′-UGUUAGAAGUCCAGGCAGA-3′(SEQ ID NO: 2928) TTR-706 19 nt Target #3: 5′-AUGUUAGAAGUCCAGGCAG-3′(SEQ ID NO: 3312) TTR-707 19 nt Target #1: 5′-UUAGAAGUCCAGGCAGAGA-3′(SEQ ID NO: 2545) TTR-707 19 nt Target #2: 5′-GUUAGAAGUCCAGGCAGAG-3′(SEQ ID NO: 2929) TTR-707 19 nt Target #3: 5′-UGUUAGAAGUCCAGGCAGA-3′(SEQ ID NO: 3313) TTR-708 19 nt Target #1: 5′-UAGAAGUCCAGGCAGAGAC-3′(SEQ ID NO: 2546) TTR-708 19 nt Target #2: 5′-UUAGAAGUCCAGGCAGAGA-3′(SEQ ID NO: 2930) TTR-708 19 nt Target #3: 5′-GUUAGAAGUCCAGGCAGAG-3′(SEQ ID NO: 3314) TTR-709 19 nt Target #1: 5′-AGAAGUCCAGGCAGAGACA-3′(SEQ ID NO: 2547) TTR-709 19 nt Target #2: 5′-UAGAAGUCCAGGCAGAGAC-3′(SEQ ID NO: 2931) TTR-709 19 nt Target #3: 5′-UUAGAAGUCCAGGCAGAGA-3′(SEQ ID NO: 3315) TTR-710 19 nt Target #1: 5′-GAAGUCCAGGCAGAGACAA-3′(SEQ ID NO: 2548) TTR-710 19 nt Target #2: 5′-AGAAGUCCAGGCAGAGACA-3′(SEQ ID NO: 2932) TTR-710 19 nt Target #3: 5′-UAGAAGUCCAGGCAGAGAC-3′(SEQ ID NO: 3316) TTR-711 19 nt Target #1: 5′-AAGUCCAGGCAGAGACAAU-3′(SEQ ID NO: 2549) TTR-711 19 nt Target #2: 5′-GAAGUCCAGGCAGAGACAA-3′(SEQ ID NO: 2933) TTR-711 19 nt Target #3: 5′-AGAAGUCCAGGCAGAGACA-3′(SEQ ID NO: 3317) TTR-712 19 nt Target #1: 5′-AGUCCAGGCAGAGACAAUA-3′(SEQ ID NO: 2550) TTR-712 19 nt Target #2: 5′-AAGUCCAGGCAGAGACAAU-3′(SEQ ID NO: 2934) TTR-712 19 nt Target #3: 5′-GAAGUCCAGGCAGAGACAA-3′(SEQ ID NO: 3318) TTR-713 19 nt Target #1: 5′-GUCCAGGCAGAGACAAUAA-3′(SEQ ID NO: 2551) TTR-713 19 nt Target #2: 5′-AGUCCAGGCAGAGACAAUA-3′(SEQ ID NO: 2935) TTR-713 19 nt Target #3: 5′-AAGUCCAGGCAGAGACAAU-3′(SEQ ID NO: 3319) TTR-714 19 nt Target #1: 5′-UCCAGGCAGAGACAAUAAA-3′(SEQ ID NO: 2552) TTR-714 19 nt Target #2: 5′-GUCCAGGCAGAGACAAUAA-3′(SEQ ID NO: 2936) TTR-714 19 nt Target #3: 5′-AGUCCAGGCAGAGACAAUA-3′(SEQ ID NO: 3320) TTR-716 19 nt Target #1: 5′-CAGGCAGAGACAAUAAAAC-3′(SEQ ID NO: 2553) TTR-716 19 nt Target #2: 5′-CCAGGCAGAGACAAUAAAA-3′(SEQ ID NO: 2937) TTR-716 19 nt Target #3: 5′-UCCAGGCAGAGACAAUAAA-3′(SEQ ID NO: 3321) TTR-717 19 nt Target #1: 5′-AGGCAGAGACAAUAAAACA-3′(SEQ ID NO: 2554) TTR-717 19 nt Target #2: 5′-CAGGCAGAGACAAUAAAAC-3′(SEQ ID NO: 2938) TTR-717 19 nt Target #3: 5′-CCAGGCAGAGACAAUAAAA-3′(SEQ ID NO: 3322) TTR-718 19 nt Target #1: 5′-GGCAGAGACAAUAAAACAU-3′(SEQ ID NO: 2555) TTR-718 19 nt Target #2: 5′-AGGCAGAGACAAUAAAACA-3′(SEQ ID NO: 2939) TTR-718 19 nt Target #3: 5′-CAGGCAGAGACAAUAAAAC-3′(SEQ ID NO: 3323) TTR-719 19 nt Target #1: 5′-GCAGAGACAAUAAAACAUU-3′(SEQ ID NO: 2556) TTR-719 19 nt Target #2: 5′-GGCAGAGACAAUAAAACAU-3′(SEQ ID NO: 2940) TTR-719 19 nt Target #3: 5′-AGGCAGAGACAAUAAAACA-3′(SEQ ID NO: 3324) TTR-720 19 nt Target #1: 5′-CAGAGACAAUAAAACAUUC-3′(SEQ ID NO: 2557) TTR-720 19 nt Target #2: 5′-GCAGAGACAAUAAAACAUU-3′(SEQ ID NO: 2941) TTR-720 19 nt Target #3: 5′-GGCAGAGACAAUAAAACAU-3′(SEQ ID NO: 3325) TTR-721 19 nt Target #1: 5′-AGAGACAAUAAAACAUUCC-3′(SEQ ID NO: 2558) TTR-721 19 nt Target #2: 5′-CAGAGACAAUAAAACAUUC-3′(SEQ ID NO: 2942) TTR-721 19 nt Target #3: 5′-GCAGAGACAAUAAAACAUU-3′(SEQ ID NO: 3326) TTR-722 19 nt Target #1: 5′-GAGACAAUAAAACAUUCCU-3′(SEQ ID NO: 2559) TTR-722 19 nt Target #2: 5′-AGAGACAAUAAAACAUUCC-3′(SEQ ID NO: 2943) TTR-722 19 nt Target #3: 5′-CAGAGACAAUAAAACAUUC-3′(SEQ ID NO: 3327) TTR-723 19 nt Target #1: 5′-AGACAAUAAAACAUUCCUG-3′(SEQ ID NO: 2560) TTR-723 19 nt Target #2: 5′-GAGACAAUAAAACAUUCCU-3′(SEQ ID NO: 2944) TTR-723 19 nt Target #3: 5′-AGAGACAAUAAAACAUUCC-3′(SEQ ID NO: 3328) TTR-724 19 nt Target #1: 5′-GACAAUAAAACAUUCCUGU-3′(SEQ ID NO: 2561) TTR-724 19 nt Target #2: 5′-AGACAAUAAAACAUUCCUG-3′(SEQ ID NO: 2945) TTR-724 19 nt Target #3: 5′-GAGACAAUAAAACAUUCCU-3′(SEQ ID NO: 3329) TTR-725 19 nt Target #1: 5′-ACAAUAAAACAUUCCUGUG-3′(SEQ ID NO: 2562) TTR-725 19 nt Target #2: 5′-GACAAUAAAACAUUCCUGU-3′(SEQ ID NO: 2946) TTR-725 19 nt Target #3: 5′-AGACAAUAAAACAUUCCUG-3′(SEQ ID NO: 3330) TTR-726 19 nt Target #1: 5′-CAAUAAAACAUUCCUGUGA-3′(SEQ ID NO: 2563) TTR-726 19 nt Target #2: 5′-ACAAUAAAACAUUCCUGUG-3′(SEQ ID NO: 2947) TTR-726 19 nt Target #3: 5′-GACAAUAAAACAUUCCUGU-3′(SEQ ID NO: 3331) TTR-727 19 nt Target #1: 5′-AAUAAAACAUUCCUGUGAA-3′(SEQ ID NO: 2564) TTR-727 19 nt Target #2: 5′-CAAUAAAACAUUCCUGUGA-3′(SEQ ID NO: 2948) TTR-727 19 nt Target #3: 5′-ACAAUAAAACAUUCCUGUG-3′(SEQ ID NO: 3332) TTR-728 19 nt Target #1: 5′-AUAAAACAUUCCUGUGAAA-3′(SEQ ID NO: 2565) TTR-728 19 nt Target #2: 5′-AAUAAAACAUUCCUGUGAA-3′(SEQ ID NO: 2949) TTR-728 19 nt Target #3: 5′-CAAUAAAACAUUCCUGUGA-3′(SEQ ID NO: 3333) TTR-731 19 nt Target #1: 5′-AAACAUUCCUGUGAAAGGC-3′(SEQ ID NO: 2566) TTR-731 19 nt Target #2: 5′-AAAACAUUCCUGUGAAAGG-3′(SEQ ID NO: 2950) TTR-731 19 nt Target #3: 5′-UAAAACAUUCCUGUGAAAG-3′(SEQ ID NO: 3334) TTR-732 19 nt Target #1: 5′-AACAUUCCUGUGAAAGGCA-3′(SEQ ID NO: 2567) TTR-732 19 nt Target #2: 5′-AAACAUUCCUGUGAAAGGC-3′(SEQ ID NO: 2951) TTR-732 19 nt Target #3: 5′-AAAACAUUCCUGUGAAAGG-3′(SEQ ID NO: 3335) TTR-733 19 nt Target #1: 5′-ACAUUCCUGUGAAAGGCAC-3′(SEQ ID NO: 2568) TTR-733 19 nt Target #2: 5′-AACAUUCCUGUGAAAGGCA-3′(SEQ ID NO: 2952) TTR-733 19 nt Target #3: 5′-AAACAUUCCUGUGAAAGGC-3′(SEQ ID NO: 3336) TTR-734 19 nt Target #1: 5′-CAUUCCUGUGAAAGGCACU-3′(SEQ ID NO: 2569) TTR-734 19 nt Target #2: 5′-ACAUUCCUGUGAAAGGCAC-3′(SEQ ID NO: 2953) TTR-734 19 nt Target #3: 5′-AACAUUCCUGUGAAAGGCA-3′(SEQ ID NO: 3337) TTR-735 19 nt Target #1: 5′-AUUCCUGUGAAAGGCACUU-3′(SEQ ID NO: 2570) TTR-735 19 nt Target #2: 5′-CAUUCCUGUGAAAGGCACU-3′(SEQ ID NO: 2954) TTR-735 19 nt Target #3: 5′-ACAUUCCUGUGAAAGGCAC-3′(SEQ ID NO: 3338) TTR-736 19 nt Target #1: 5′-UUCCUGUGAAAGGCACUUU-3′(SEQ ID NO: 2571) TTR-736 19 nt Target #2: 5′-AUUCCUGUGAAAGGCACUU-3′(SEQ ID NO: 2955) TTR-736 19 nt Target #3: 5′-CAUUCCUGUGAAAGGCACU-3′(SEQ ID NO: 3339) TTR-738 19 nt Target #1: 5′-CCUGUGAAAGGCACUUUUC-3′(SEQ ID NO: 2572) TTR-738 19 nt Target #2: 5′-UCCUGUGAAAGGCACUUUU-3′(SEQ ID NO: 2956) TTR-738 19 nt Target #3: 5′-UUCCUGUGAAAGGCACUUU-3′(SEQ ID NO: 3340) TTR-739 19 nt Target #1: 5′-CUGUGAAAGGCACUUUUCA-3′(SEQ ID NO: 2573) TTR-739 19 nt Target #2: 5′-CCUGUGAAAGGCACUUUUC-3′(SEQ ID NO: 2957) TTR-739 19 nt Target #3: 5′-UCCUGUGAAAGGCACUUUU-3′(SEQ ID NO: 3341) TTR-740 19 nt Target #1: 5′-UGUGAAAGGCACUUUUCAU-3′(SEQ ID NO: 2574) TTR-740 19 nt Target #2: 5′-CUGUGAAAGGCACUUUUCA-3′(SEQ ID NO: 2958) TTR-740 19 nt Target #3: 5′-CCUGUGAAAGGCACUUUUC-3′(SEQ ID NO: 3342) TTR-741 19 nt Target #1: 5′-GUGAAAGGCACUUUUCAUU-3′(SEQ ID NO: 2575) TTR-741 19 nt Target #2: 5′-UGUGAAAGGCACUUUUCAU-3′(SEQ ID NO: 2959) TTR-741 19 nt Target #3: 5′-CUGUGAAAGGCACUUUUCA-3′(SEQ ID NO: 3343) TTR-742 19 nt Target #1: 5′-UGAAAGGCACUUUUCAUUC-3′(SEQ ID NO: 2576) TTR-742 19 nt Target #2: 5′-GUGAAAGGCACUUUUCAUU-3′(SEQ ID NO: 2960) TTR-742 19 nt Target #3: 5′-UGUGAAAGGCACUUUUCAU-3′(SEQ ID NO: 3344) TTR-743 19 nt Target #1: 5′-GAAAGGCACUUUUCAUUCC-3′(SEQ ID NO: 2577) TTR-743 19 nt Target #2: 5′-UGAAAGGCACUUUUCAUUC-3′(SEQ ID NO: 2961) TTR-743 19 nt Target #3: 5′-GUGAAAGGCACUUUUCAUU-3′(SEQ ID NO: 3345) TTR-744 19 nt Target #1: 5′-AAAGGCACUUUUCAUUCCA-3′(SEQ ID NO: 2578) TTR-744 19 nt Target #2: 5′-GAAAGGCACUUUUCAUUCC-3′(SEQ ID NO: 2962) TTR-744 19 nt Target #3: 5′-UGAAAGGCACUUUUCAUUC-3′(SEQ ID NO: 3346) TTR-745 19 nt Target #1: 5′-AAGGCACUUUUCAUUCCAC-3′(SEQ ID NO: 2579) TTR-745 19 nt Target #2: 5′-AAAGGCACUUUUCAUUCCA-3′(SEQ ID NO: 2963) TTR-745 19 nt Target #3: 5′-GAAAGGCACUUUUCAUUCC-3′(SEQ ID NO: 3347) TTR-746 19 nt Target #1: 5′-AGGCACUUUUCAUUCCACU-3′(SEQ ID NO: 2580) TTR-746 19 nt Target #2: 5′-AAGGCACUUUUCAUUCCAC-3′(SEQ ID NO: 2964) TTR-746 19 nt Target #3: 5′-AAAGGCACUUUUCAUUCCA-3′(SEQ ID NO: 3348) TTR-747 19 nt Target #1: 5′-GGCACUUUUCAUUCCACUU-3′(SEQ ID NO: 2581) TTR-747 19 nt Target #2: 5′-AGGCACUUUUCAUUCCACU-3′(SEQ ID NO: 2965) TTR-747 19 nt Target #3: 5′-AAGGCACUUUUCAUUCCAC-3′(SEQ ID NO: 3349) TTR-748 19 nt Target #1: 5′-GCACUUUUCAUUCCACUUU-3′(SEQ ID NO: 2582) TTR-748 19 nt Target #2: 5′-GGCACUUUUCAUUCCACUU-3′(SEQ ID NO: 2966) TTR-748 19 nt Target #3: 5′-AGGCACUUUUCAUUCCACU-3′(SEQ ID NO: 3350) TTR-749 19 nt Target #1: 5′-CACUUUUCAUUCCACUUUA-3′(SEQ ID NO: 2583) TTR-749 19 nt Target #2: 5′-GCACUUUUCAUUCCACUUU-3′(SEQ ID NO: 2967) TTR-749 19 nt Target #3: 5′-GGCACUUUUCAUUCCACUU-3′(SEQ ID NO: 3351) TTR-750 19 nt Target #1: 5′-ACUUUUCAUUCCACUUUAA-3′(SEQ ID NO: 2584) TTR-750 19 nt Target #2: 5′-CACUUUUCAUUCCACUUUA-3′(SEQ ID NO: 2968) TTR-750 19 nt Target #3: 5′-GCACUUUUCAUUCCACUUU-3′(SEQ ID NO: 3352) TTR-751 19 nt Target #1: 5′-CUUUUCAUUCCACUUUAAC-3′(SEQ ID NO: 2585) TTR-751 19 nt Target #2: 5′-ACUUUUCAUUCCACUUUAA-3′(SEQ ID NO: 2969) TTR-751 19 nt Target #3: 5′-CACUUUUCAUUCCACUUUA-3′(SEQ ID NO: 3353) TTR-752 19 nt Target #1: 5′-UUUUCAUUCCACUUUAACU-3′(SEQ ID NO: 2586) TTR-752 19 nt Target #2: 5′-CUUUUCAUUCCACUUUAAC-3′(SEQ ID NO: 2970) TTR-752 19 nt Target #3: 5′-ACUUUUCAUUCCACUUUAA-3′(SEQ ID NO: 3354) TTR-753 19 nt Target #1: 5′-UUUCAUUCCACUUUAACUU-3′(SEQ ID NO: 2587) TTR-753 19 nt Target #2: 5′-UUUUCAUUCCACUUUAACU-3′(SEQ ID NO: 2971) TTR-753 19 nt Target #3: 5′-CUUUUCAUUCCACUUUAAC-3′(SEQ ID NO: 3355) TTR-754 19 nt Target #1: 5′-UUCAUUCCACUUUAACUUG-3′(SEQ ID NO: 2588) TTR-754 19 nt Target #2: 5′-UUUCAUUCCACUUUAACUU-3′(SEQ ID NO: 2972) TTR-754 19 nt Target #3: 5′-UUUUCAUUCCACUUUAACU-3′(SEQ ID NO: 3356) TTR-755 19 nt Target #1: 5′-UCAUUCCACUUUAACUUGA-3′(SEQ ID NO: 2589) TTR-755 19 nt Target #2: 5′-UUCAUUCCACUUUAACUUG-3′(SEQ ID NO: 2973) TTR-755 19 nt Target #3: 5′-UUUCAUUCCACUUUAACUU-3′(SEQ ID NO: 3357) TTR-756 19 nt Target #1: 5′-CAUUCCACUUUAACUUGAU-3′(SEQ ID NO: 2590) TTR-756 19 nt Target #2: 5′-UCAUUCCACUUUAACUUGA-3′(SEQ ID NO: 2974) TTR-756 19 nt Target #3: 5′-UUCAUUCCACUUUAACUUG-3′(SEQ ID NO: 3358) TTR-757 19 nt Target #1: 5′-AUUCCACUUUAACUUGAUU-3′(SEQ ID NO: 2591) TTR-757 19 nt Target #2: 5′-CAUUCCACUUUAACUUGAU-3′(SEQ ID NO: 2975) TTR-757 19 nt Target #3: 5′-UCAUUCCACUUUAACUUGA-3′(SEQ ID NO: 3359) TTR-758 19 nt Target #1: 5′-UUCCACUUUAACUUGAUUU-3′(SEQ ID NO: 2592) TTR-758 19 nt Target #2: 5′-AUUCCACUUUAACUUGAUU-3′(SEQ ID NO: 2976) TTR-758 19 nt Target #3: 5′-CAUUCCACUUUAACUUGAU-3′(SEQ ID NO: 3360) TTR-759 19 nt Target #1: 5′-UCCACUUUAACUUGAUUUU-3′(SEQ ID NO: 2593) TTR-759 19 nt Target #2: 5′-UUCCACUUUAACUUGAUUU-3′(SEQ ID NO: 2977) TTR-759 19 nt Target #3: 5′-AUUCCACUUUAACUUGAUU-3′(SEQ ID NO: 3361) TTR-760 19 nt Target #1: 5′-CCACUUUAACUUGAUUUUU-3′(SEQ ID NO: 2594) TTR-760 19 nt Target #2: 5′-UCCACUUUAACUUGAUUUU-3′(SEQ ID NO: 2978) TTR-760 19 nt Target #3: 5′-UUCCACUUUAACUUGAUUU-3′(SEQ ID NO: 3362) TTR-761 19 nt Target #1: 5′-CACUUUAACUUGAUUUUUU-3′(SEQ ID NO: 2595) TTR-761 19 nt Target #2: 5′-CCACUUUAACUUGAUUUUU-3′(SEQ ID NO: 2979) TTR-761 19 nt Target #3: 5′-UCCACUUUAACUUGAUUUU-3′(SEQ ID NO: 3363) TTR-762 19 nt Target #1: 5′-ACUUUAACUUGAUUUUUUA-3′(SEQ ID NO: 2596) TTR-762 19 nt Target #2: 5′-CACUUUAACUUGAUUUUUU-3′(SEQ ID NO: 2980) TTR-762 19 nt Target #3: 5′-CCACUUUAACUUGAUUUUU-3′(SEQ ID NO: 3364) TTR-763 19 nt Target #1: 5′-CUUUAACUUGAUUUUUUAA-3′(SEQ ID NO: 2597) TTR-763 19 nt Target #2: 5′-ACUUUAACUUGAUUUUUUA-3′(SEQ ID NO: 2981) TTR-763 19 nt Target #3: 5′-CACUUUAACUUGAUUUUUU-3′(SEQ ID NO: 3365) TTR-764 19 nt Target #1: 5′-UUUAACUUGAUUUUUUAAA-3′(SEQ ID NO: 2598) TTR-764 19 nt Target #2: 5′-CUUUAACUUGAUUUUUUAA-3′(SEQ ID NO: 2982) TTR-764 19 nt Target #3: 5′-ACUUUAACUUGAUUUUUUA-3′(SEQ ID NO: 3366) TTR-765 19 nt Target #1: 5′-UUAACUUGAUUUUUUAAAU-3′(SEQ ID NO: 2599) TTR-765 19 nt Target #2: 5′-UUUAACUUGAUUUUUUAAA-3′(SEQ ID NO: 2983) TTR-765 19 nt Target #3: 5′-CUUUAACUUGAUUUUUUAA-3′(SEQ ID NO: 3367) TTR-766 19 nt Target #1: 5′-UAACUUGAUUUUUUAAAUU-3′(SEQ ID NO: 2600) TTR-766 19 nt Target #2: 5′-UUAACUUGAUUUUUUAAAU-3′(SEQ ID NO: 2984) TTR-766 19 nt Target #3: 5′-UUUAACUUGAUUUUUUAAA-3′(SEQ ID NO: 3368) TTR-767 19 nt Target #1: 5′-AACUUGAUUUUUUAAAUUC-3′(SEQ ID NO: 2601) TTR-767 19 nt Target #2: 5′-UAACUUGAUUUUUUAAAUU-3′(SEQ ID NO: 2985) TTR-767 19 nt Target #3: 5′-UUAACUUGAUUUUUUAAAU-3′(SEQ ID NO: 3369) TTR-768 19 nt Target #1: 5′-ACUUGAUUUUUUAAAUUCC-3′(SEQ ID NO: 2602) TTR-768 19 nt Target #2: 5′-AACUUGAUUUUUUAAAUUC-3′(SEQ ID NO: 2986) TTR-768 19 nt Target #3: 5′-UAACUUGAUUUUUUAAAUU-3′(SEQ ID NO: 3370) TTR-769 19 nt Target #1: 5′-CUUGAUUUUUUAAAUUCCC-3′(SEQ ID NO: 2603) TTR-769 19 nt Target #2: 5′-ACUUGAUUUUUUAAAUUCC-3′(SEQ ID NO: 2987) TTR-769 19 nt Target #3: 5′-AACUUGAUUUUUUAAAUUC-3′(SEQ ID NO: 3371) TTR-770 19 nt Target #1: 5′-UUGAUUUUUUAAAUUCCCU-3′(SEQ ID NO: 2604) TTR-770 19 nt Target #2: 5′-CUUGAUUUUUUAAAUUCCC-3′(SEQ ID NO: 2988) TTR-770 19 nt Target #3: 5′-ACUUGAUUUUUUAAAUUCC-3′(SEQ ID NO: 3372) TTR-771 19 nt Target #1: 5′-UGAUUUUUUAAAUUCCCUU-3′(SEQ ID NO: 2605) TTR-771 19 nt Target #2: 5′-UUGAUUUUUUAAAUUCCCU-3′(SEQ ID NO: 2989) TTR-771 19 nt Target #3: 5′-CUUGAUUUUUUAAAUUCCC-3′(SEQ ID NO: 3373) TTR-772 19 nt Target #1: 5′-GAUUUUUUAAAUUCCCUUA-3′(SEQ ID NO: 2606) TTR-772 19 nt Target #2: 5′-UGAUUUUUUAAAUUCCCUU-3′(SEQ ID NO: 2990) TTR-772 19 nt Target #3: 5′-UUGAUUUUUUAAAUUCCCU-3′(SEQ ID NO: 3374) TTR-773 19 nt Target #1: 5′-AUUUUUUAAAUUCCCUUAU-3′(SEQ ID NO: 2607) TTR-773 19 nt Target #2: 5′-GAUUUUUUAAAUUCCCUUA-3′(SEQ ID NO: 2991) TTR-773 19 nt Target #3: 5′-UGAUUUUUUAAAUUCCCUU-3′(SEQ ID NO: 3375) TTR-775 19 nt Target #1: 5′-UUUUUAAAUUCCCUUAUUG-3′(SEQ ID NO: 2608) TTR-775 19 nt Target #2: 5′-UUUUUUAAAUUCCCUUAUU-3′(SEQ ID NO: 2992) TTR-775 19 nt Target #3: 5′-AUUUUUUAAAUUCCCUUAU-3′(SEQ ID NO: 3376) TTR-780 19 nt Target #1: 5′-AAAUUCCCUUAUUGUCCCU-3′(SEQ ID NO: 2609) TTR-780 19 nt Target #2: 5′-UAAAUUCCCUUAUUGUCCC-3′(SEQ ID NO: 2993) TTR-780 19 nt Target #3: 5′-UUAAAUUCCCUUAUUGUCC-3′(SEQ ID NO: 3377) TTR-781 19 nt Target #1: 5′-AAUUCCCUUAUUGUCCCUU-3′(SEQ ID NO: 2610) TTR-781 19 nt Target #2: 5′-AAAUUCCCUUAUUGUCCCU-3′(SEQ ID NO: 2994) TTR-781 19 nt Target #3: 5′-UAAAUUCCCUUAUUGUCCC-3′(SEQ ID NO: 3378) TTR-784 19 nt Target #1: 5′-UCCCUUAUUGUCCCUUCCA-3′(SEQ ID NO: 2611) TTR-784 19 nt Target #2: 5′-UUCCCUUAUUGUCCCUUCC-3′(SEQ ID NO: 2995) TTR-784 19 nt Target #3: 5′-AUUCCCUUAUUGUCCCUUC-3′(SEQ ID NO: 3379) TTR-805 19 nt Target #1: 5′-AAAAAGAGAAUCAAAAUUU-3′(SEQ ID NO: 2612) TTR-805 19 nt Target #2: 5′-AAAAAAGAGAAUCAAAAUU-3′(SEQ ID NO: 2996) TTR-805 19 nt Target #3: 5′-AAAAAAAGAGAAUCAAAAU-3′(SEQ ID NO: 3380) TTR-806 19 nt Target #1: 5′-AAAAGAGAAUCAAAAUUUU-3′(SEQ ID NO: 2613) TTR-806 19 nt Target #2: 5′-AAAAAGAGAAUCAAAAUUU-3′(SEQ ID NO: 2997) TTR-806 19 nt Target #3: 5′-AAAAAAGAGAAUCAAAAUU-3′(SEQ ID NO: 3381) TTR-807 19 nt Target #1: 5′-AAAGAGAAUCAAAAUUUUA-3′(SEQ ID NO: 2614) TTR-807 19 nt Target #2: 5′-AAAAGAGAAUCAAAAUUUU-3′(SEQ ID NO: 2998) TTR-807 19 nt Target #3: 5′-AAAAAGAGAAUCAAAAUUU-3′(SEQ ID NO: 3382) TTR-808 19 nt Target #1: 5′-AAGAGAAUCAAAAUUUUAC-3′(SEQ ID NO: 2615) TTR-808 19 nt Target #2: 5′-AAAGAGAAUCAAAAUUUUA-3′(SEQ ID NO: 2999) TTR-808 19 nt Target #3: 5′-AAAAGAGAAUCAAAAUUUU-3′(SEQ ID NO: 3383) TTR-809 19 nt Target #1: 5′-AGAGAAUCAAAAUUUUACA-3′(SEQ ID NO: 2616) TTR-809 19 nt Target #2: 5′-AAGAGAAUCAAAAUUUUAC-3′(SEQ ID NO: 3000) TTR-809 19 nt Target #3: 5′-AAAGAGAAUCAAAAUUUUA-3′(SEQ ID NO: 3384) TTR-810 19 nt Target #1: 5′-GAGAAUCAAAAUUUUACAA-3′(SEQ ID NO: 2617) TTR-810 19 nt Target #2: 5′-AGAGAAUCAAAAUUUUACA-3′(SEQ ID NO: 3001) TTR-810 19 nt Target #3: 5′-AAGAGAAUCAAAAUUUUAC-3′(SEQ ID NO: 3385) TTR-811 19 nt Target #1: 5′-AGAAUCAAAAUUUUACAAA-3′(SEQ ID NO: 2618) TTR-811 19 nt Target #2: 5′-GAGAAUCAAAAUUUUACAA-3′(SEQ ID NO: 3002) TTR-811 19 nt Target #3: 5′-AGAGAAUCAAAAUUUUACA-3′(SEQ ID NO: 3386) TTR-812 19 nt Target #1: 5′-GAAUCAAAAUUUUACAAAG-3′(SEQ ID NO: 2619) TTR-812 19 nt Target #2: 5′-AGAAUCAAAAUUUUACAAA-3′(SEQ ID NO: 3003) TTR-812 19 nt Target #3: 5′-GAGAAUCAAAAUUUUACAA-3′(SEQ ID NO: 3387) TTR-813 19 nt Target #1: 5′-AAUCAAAAUUUUACAAAGA-3′(SEQ ID NO: 2620) TTR-813 19 nt Target #2: 5′-GAAUCAAAAUUUUACAAAG-3′(SEQ ID NO: 3004) TTR-813 19 nt Target #3: 5′-AGAAUCAAAAUUUUACAAA-3′(SEQ ID NO: 3388) TTR-814 19 nt Target #1: 5′-AUCAAAAUUUUACAAAGAA-3′(SEQ ID NO: 2621) TTR-814 19 nt Target #2: 5′-AAUCAAAAUUUUACAAAGA-3′(SEQ ID NO: 3005) TTR-814 19 nt Target #3: 5′-GAAUCAAAAUUUUACAAAG-3′(SEQ ID NO: 3389) TTR-815 19 nt Target #1: 5′-UCAAAAUUUUACAAAGAAU-3′(SEQ ID NO: 2622) TTR-815 19 nt Target #2: 5′-AUCAAAAUUUUACAAAGAA-3′(SEQ ID NO: 3006) TTR-815 19 nt Target #3: 5′-AAUCAAAAUUUUACAAAGA-3′(SEQ ID NO: 3390) TTR-816 19 nt Target #1: 5′-CAAAAUUUUACAAAGAAUC-3′(SEQ ID NO: 2623) TTR-816 19 nt Target #2: 5′-UCAAAAUUUUACAAAGAAU-3′(SEQ ID NO: 3007) TTR-816 19 nt Target #3: 5′-AUCAAAAUUUUACAAAGAA-3′(SEQ ID NO: 3391) TTR-817 19 nt Target #1: 5′-AAAAUUUUACAAAGAAUCA-3′(SEQ ID NO: 2624) TTR-817 19 nt Target #2: 5′-CAAAAUUUUACAAAGAAUC-3′(SEQ ID NO: 3008) TTR-817 19 nt Target #3: 5′-UCAAAAUUUUACAAAGAAU-3′(SEQ ID NO: 3392) TTR-818 19 nt Target #1: 5′-AAAUUUUACAAAGAAUCAA-3′(SEQ ID NO: 2625) TTR-818 19 nt Target #2: 5′-AAAAUUUUACAAAGAAUCA-3′(SEQ ID NO: 3009) TTR-818 19 nt Target #3: 5′-CAAAAUUUUACAAAGAAUC-3′(SEQ ID NO: 3393) TTR-819 19 nt Target #1: 5′-AAUUUUACAAAGAAUCAAA-3′(SEQ ID NO: 2626) TTR-819 19 nt Target #2: 5′-AAAUUUUACAAAGAAUCAA-3′(SEQ ID NO: 3010) TTR-819 19 nt Target #3: 5′-AAAAUUUUACAAAGAAUCA-3′(SEQ ID NO: 3394) TTR-821 19 nt Target #1: 5′-UUUUACAAAGAAUCAAAGG-3′(SEQ ID NO: 2627) TTR-821 19 nt Target #2: 5′-AUUUUACAAAGAAUCAAAG-3′(SEQ ID NO: 3011) TTR-821 19 nt Target #3: 5′-AAUUUUACAAAGAAUCAAA-3′(SEQ ID NO: 3395) TTR-822 19 nt Target #1: 5′-UUUACAAAGAAUCAAAGGA-3′(SEQ ID NO: 2628) TTR-822 19 nt Target #2: 5′-UUUUACAAAGAAUCAAAGG-3′(SEQ ID NO: 3012) TTR-822 19 nt Target #3: 5′-AUUUUACAAAGAAUCAAAG-3′(SEQ ID NO: 3396) TTR-823 19 nt Target #1: 5′-UUACAAAGAAUCAAAGGAA-3′(SEQ ID NO: 2629) TTR-823 19 nt Target #2: 5′-UUUACAAAGAAUCAAAGGA-3′(SEQ ID NO: 3013) TTR-823 19 nt Target #3: 5′-UUUUACAAAGAAUCAAAGG-3′(SEQ ID NO: 3397) TTR-824 19 nt Target #1: 5′-UACAAAGAAUCAAAGGAAU-3′(SEQ ID NO: 2630) TTR-824 19 nt Target #2: 5′-UUACAAAGAAUCAAAGGAA-3′(SEQ ID NO: 3014) TTR-824 19 nt Target #3: 5′-UUUACAAAGAAUCAAAGGA-3′(SEQ ID NO: 3398) TTR-825 19 nt Target #1: 5′-ACAAAGAAUCAAAGGAAUU-3′(SEQ ID NO: 2631) TTR-825 19 nt Target #2: 5′-UACAAAGAAUCAAAGGAAU-3′(SEQ ID NO: 3015) TTR-825 19 nt Target #3: 5′-UUACAAAGAAUCAAAGGAA-3′(SEQ ID NO: 3399) TTR-826 19 nt Target #1: 5′-CAAAGAAUCAAAGGAAUUC-3′(SEQ ID NO: 2632) TTR-826 19 nt Target #2: 5′-ACAAAGAAUCAAAGGAAUU-3′(SEQ ID NO: 3016) TTR-826 19 nt Target #3: 5′-UACAAAGAAUCAAAGGAAU-3′(SEQ ID NO: 3400) TTR-827 19 nt Target #1: 5′-AAAGAAUCAAAGGAAUUCU-3′(SEQ ID NO: 2633) TTR-827 19 nt Target #2: 5′-CAAAGAAUCAAAGGAAUUC-3′(SEQ ID NO: 3017) TTR-827 19 nt Target #3: 5′-ACAAAGAAUCAAAGGAAUU-3′(SEQ ID NO: 3401) TTR-828 19 nt Target #1: 5′-AAGAAUCAAAGGAAUUCUA-3′(SEQ ID NO: 2634) TTR-828 19 nt Target #2: 5′-AAAGAAUCAAAGGAAUUCU-3′(SEQ ID NO: 3018) TTR-828 19 nt Target #3: 5′-CAAAGAAUCAAAGGAAUUC-3′(SEQ ID NO: 3402) TTR-829 19 nt Target #1: 5′-AGAAUCAAAGGAAUUCUAG-3′(SEQ ID NO: 2635) TTR-829 19 nt Target #2: 5′-AAGAAUCAAAGGAAUUCUA-3′(SEQ ID NO: 3019) TTR-829 19 nt Target #3: 5′-AAAGAAUCAAAGGAAUUCU-3′(SEQ ID NO: 3403) TTR-830 19 nt Target #1: 5′-GAAUCAAAGGAAUUCUAGA-3′(SEQ ID NO: 2636) TTR-830 19 nt Target #2: 5′-AGAAUCAAAGGAAUUCUAG-3′(SEQ ID NO: 3020) TTR-830 19 nt Target #3: 5′-AAGAAUCAAAGGAAUUCUA-3′(SEQ ID NO: 3404) TTR-831 19 nt Target #1: 5′-AAUCAAAGGAAUUCUAGAA-3′(SEQ ID NO: 2637) TTR-831 19 nt Target #2: 5′-GAAUCAAAGGAAUUCUAGA-3′(SEQ ID NO: 3021) TTR-831 19 nt Target #3: 5′-AGAAUCAAAGGAAUUCUAG-3′(SEQ ID NO: 3405) TTR-832 19 nt Target #1: 5′-AUCAAAGGAAUUCUAGAAA-3′(SEQ ID NO: 2638) TTR-832 19 nt Target #2: 5′-AAUCAAAGGAAUUCUAGAA-3′(SEQ ID NO: 3022) TTR-832 19 nt Target #3: 5′-GAAUCAAAGGAAUUCUAGA-3′(SEQ ID NO: 3406) TTR-833 19 nt Target #1: 5′-UCAAAGGAAUUCUAGAAAG-3′(SEQ ID NO: 2639) TTR-833 19 nt Target #2: 5′-AUCAAAGGAAUUCUAGAAA-3′(SEQ ID NO: 3023) TTR-833 19 nt Target #3: 5′-AAUCAAAGGAAUUCUAGAA-3′(SEQ ID NO: 3407) TTR-834 19 nt Target #1: 5′-CAAAGGAAUUCUAGAAAGU-3′(SEQ ID NO: 2640) TTR-834 19 nt Target #2: 5′-UCAAAGGAAUUCUAGAAAG-3′(SEQ ID NO: 3024) TTR-834 19 nt Target #3: 5′-AUCAAAGGAAUUCUAGAAA-3′(SEQ ID NO: 3408) TTR-835 19 nt Target #1: 5′-AAAGGAAUUCUAGAAAGUA-3′(SEQ ID NO: 2641) TTR-835 19 nt Target #2: 5′-CAAAGGAAUUCUAGAAAGU-3′(SEQ ID NO: 3025) TTR-835 19 nt Target #3: 5′-UCAAAGGAAUUCUAGAAAG-3′(SEQ ID NO: 3409) TTR-869 19 nt Target #1: 5′-AGGAGAGAUCCAAAUUUCC-3′(SEQ ID NO: 2642) TTR-869 19 nt Target #2: 5′-UAGGAGAGAUCCAAAUUUC-3′(SEQ ID NO: 3026) TTR-869 19 nt Target #3: 5′-CUAGGAGAGAUCCAAAUUU-3′(SEQ ID NO: 3410) TTR-870 19 nt Target #1: 5′-GGAGAGAUCCAAAUUUCCA-3′(SEQ ID NO: 2643) TTR-870 19 nt Target #2: 5′-AGGAGAGAUCCAAAUUUCC-3′(SEQ ID NO: 3027) TTR-870 19 nt Target #3: 5′-UAGGAGAGAUCCAAAUUUC-3′(SEQ ID NO: 3411) TTR-873 19 nt Target #1: 5′-GAGAUCCAAAUUUCCAUUG-3′(SEQ ID NO: 2644) TTR-873 19 nt Target #2: 5′-AGAGAUCCAAAUUUCCAUU-3′(SEQ ID NO: 3028) TTR-873 19 nt Target #3: 5′-GAGAGAUCCAAAUUUCCAU-3′(SEQ ID NO: 3412) TTR-874 19 nt Target #1: 5′-AGAUCCAAAUUUCCAUUGU-3′(SEQ ID NO: 2645) TTR-874 19 nt Target #2: 5′-GAGAUCCAAAUUUCCAUUG-3′(SEQ ID NO: 3029) TTR-874 19 nt Target #3: 5′-AGAGAUCCAAAUUUCCAUU-3′(SEQ ID NO: 3413) TTR-875 19 nt Target #1: 5′-GAUCCAAAUUUCCAUUGUC-3′(SEQ ID NO: 2646) TTR-875 19 nt Target #2: 5′-AGAUCCAAAUUUCCAUUGU-3′(SEQ ID NO: 3030) TTR-875 19 nt Target #3: 5′-GAGAUCCAAAUUUCCAUUG-3′(SEQ ID NO: 3414) TTR-876 19 nt Target #1: 5′-AUCCAAAUUUCCAUUGUCU-3′(SEQ ID NO: 2647) TTR-876 19 nt Target #2: 5′-GAUCCAAAUUUCCAUUGUC-3′(SEQ ID NO: 3031) TTR-876 19 nt Target #3: 5′-AGAUCCAAAUUUCCAUUGU-3′(SEQ ID NO: 3415) TTR-877 19 nt Target #1: 5′-UCCAAAUUUCCAUUGUCUU-3′(SEQ ID NO: 2648) TTR-877 19 nt Target #2: 5′-AUCCAAAUUUCCAUUGUCU-3′(SEQ ID NO: 3032) TTR-877 19 nt Target #3: 5′-GAUCCAAAUUUCCAUUGUC-3′(SEQ ID NO: 3416) TTR-878 19 nt Target #1: 5′-CCAAAUUUCCAUUGUCUUG-3′(SEQ ID NO: 2649) TTR-878 19 nt Target #2: 5′-UCCAAAUUUCCAUUGUCUU-3′(SEQ ID NO: 3033) TTR-878 19 nt Target #3: 5′-AUCCAAAUUUCCAUUGUCU-3′(SEQ ID NO: 3417) TTR-879 19 nt Target #1: 5′-CAAAUUUCCAUUGUCUUGC-3′(SEQ ID NO: 2650) TTR-879 19 nt Target #2: 5′-CCAAAUUUCCAUUGUCUUG-3′(SEQ ID NO: 3034) TTR-879 19 nt Target #3: 5′-UCCAAAUUUCCAUUGUCUU-3′(SEQ ID NO: 3418) TTR-880 19 nt Target #1: 5′-AAAUUUCCAUUGUCUUGCA-3′(SEQ ID NO: 2651) TTR-880 19 nt Target #2: 5′-CAAAUUUCCAUUGUCUUGC-3′(SEQ ID NO: 3035) TTR-880 19 nt Target #3: 5′-CCAAAUUUCCAUUGUCUUG-3′(SEQ ID NO: 3419) TTR-881 19 nt Target #1: 5′-AAUUUCCAUUGUCUUGCAA-3′(SEQ ID NO: 2652) TTR-881 19 nt Target #2: 5′-AAAUUUCCAUUGUCUUGCA-3′(SEQ ID NO: 3036) TTR-881 19 nt Target #3: 5′-CAAAUUUCCAUUGUCUUGC-3′(SEQ ID NO: 3420) TTR-882 19 nt Target #1: 5′-AUUUCCAUUGUCUUGCAAG-3′(SEQ ID NO: 2653) TTR-882 19 nt Target #2: 5′-AAUUUCCAUUGUCUUGCAA-3′(SEQ ID NO: 3037) TTR-882 19 nt Target #3: 5′-AAAUUUCCAUUGUCUUGCA-3′(SEQ ID NO: 3421) TTR-883 19 nt Target #1: 5′-UUUCCAUUGUCUUGCAAGC-3′(SEQ ID NO: 2654) TTR-883 19 nt Target #2: 5′-AUUUCCAUUGUCUUGCAAG-3′(SEQ ID NO: 3038) TTR-883 19 nt Target #3: 5′-AAUUUCCAUUGUCUUGCAA-3′(SEQ ID NO: 3422) TTR-884 19 nt Target #1: 5′-UUCCAUUGUCUUGCAAGCA-3′(SEQ ID NO: 2655) TTR-884 19 nt Target #2: 5′-UUUCCAUUGUCUUGCAAGC-3′(SEQ ID NO: 3039) TTR-884 19 nt Target #3: 5′-AUUUCCAUUGUCUUGCAAG-3′(SEQ ID NO: 3423) TTR-885 19 nt Target #1: 5′-UCCAUUGUCUUGCAAGCAA-3′(SEQ ID NO: 2656) TTR-885 19 nt Target #2: 5′-UUCCAUUGUCUUGCAAGCA-3′(SEQ ID NO: 3040) TTR-885 19 nt Target #3: 5′-UUUCCAUUGUCUUGCAAGC-3′(SEQ ID NO: 3424) TTR-886 19 nt Target #1: 5′-CCAUUGUCUUGCAAGCAAA-3′(SEQ ID NO: 2657) TTR-886 19 nt Target #2: 5′-UCCAUUGUCUUGCAAGCAA-3′(SEQ ID NO: 3041) TTR-886 19 nt Target #3: 5′-UUCCAUUGUCUUGCAAGCA-3′(SEQ ID NO: 3425) TTR-887 19 nt Target #1: 5′-CAUUGUCUUGCAAGCAAAG-3′(SEQ ID NO: 2658) TTR-887 19 nt Target #2: 5′-CCAUUGUCUUGCAAGCAAA-3′(SEQ ID NO: 3042) TTR-887 19 nt Target #3: 5′-UCCAUUGUCUUGCAAGCAA-3′(SEQ ID NO: 3426) TTR-888 19 nt Target #1: 5′-AUUGUCUUGCAAGCAAAGC-3′(SEQ ID NO: 2659) TTR-888 19 nt Target #2: 5′-CAUUGUCUUGCAAGCAAAG-3′(SEQ ID NO: 3043) TTR-888 19 nt Target #3: 5′-CCAUUGUCUUGCAAGCAAA-3′(SEQ ID NO: 3427) TTR-889 19 nt Target #1: 5′-UUGUCUUGCAAGCAAAGCA-3′(SEQ ID NO: 2660) TTR-889 19 nt Target #2: 5′-AUUGUCUUGCAAGCAAAGC-3′(SEQ ID NO: 3044) TTR-889 19 nt Target #3: 5′-CAUUGUCUUGCAAGCAAAG-3′(SEQ ID NO: 3428) TTR-890 19 nt Target #1: 5′-UGUCUUGCAAGCAAAGCAC-3′(SEQ ID NO: 2661) TTR-890 19 nt Target #2: 5′-UUGUCUUGCAAGCAAAGCA-3′(SEQ ID NO: 3045) TTR-890 19 nt Target #3: 5′-AUUGUCUUGCAAGCAAAGC-3′(SEQ ID NO: 3429) TTR-891 19 nt Target #1: 5′-GUCUUGCAAGCAAAGCACG-3′(SEQ ID NO: 2662) TTR-891 19 nt Target #2: 5′-UGUCUUGCAAGCAAAGCAC-3′(SEQ ID NO: 3046) TTR-891 19 nt Target #3: 5′-UUGUCUUGCAAGCAAAGCA-3′(SEQ ID NO: 3430) TTR-892 19 nt Target #1: 5′-UCUUGCAAGCAAAGCACGU-3′(SEQ ID NO: 2663) TTR-892 19 nt Target #2: 5′-GUCUUGCAAGCAAAGCACG-3′(SEQ ID NO: 3047) TTR-892 19 nt Target #3: 5′-UGUCUUGCAAGCAAAGCAC-3′(SEQ ID NO: 3431) TTR-893 19 nt Target #1: 5′-CUUGCAAGCAAAGCACGUA-3′(SEQ ID NO: 2664) TTR-893 19 nt Target #2: 5′-UCUUGCAAGCAAAGCACGU-3′(SEQ ID NO: 3048) TTR-893 19 nt Target #3: 5′-GUCUUGCAAGCAAAGCACG-3′(SEQ ID NO: 3432) TTR-894 19 nt Target #1: 5′-UUGCAAGCAAAGCACGUAU-3′(SEQ ID NO: 2665) TTR-894 19 nt Target #2: 5′-CUUGCAAGCAAAGCACGUA-3′(SEQ ID NO: 3049) TTR-894 19 nt Target #3: 5′-UCUUGCAAGCAAAGCACGU-3′(SEQ ID NO: 3433) TTR-895 19 nt Target #1: 5′-UGCAAGCAAAGCACGUAUU-3′(SEQ ID NO: 2666) TTR-895 19 nt Target #2: 5′-UUGCAAGCAAAGCACGUAU-3′(SEQ ID NO: 3050) TTR-895 19 nt Target #3: 5′-CUUGCAAGCAAAGCACGUA-3′(SEQ ID NO: 3434) TTR-896 19 nt Target #1: 5′-GCAAGCAAAGCACGUAUUA-3′(SEQ ID NO: 2667) TTR-896 19 nt Target #2: 5′-UGCAAGCAAAGCACGUAUU-3′(SEQ ID NO: 3051) TTR-896 19 nt Target #3: 5′-UUGCAAGCAAAGCACGUAU-3′(SEQ ID NO: 3435) TTR-897 19 nt Target #1: 5′-CAAGCAAAGCACGUAUUAA-3′(SEQ ID NO: 2668) TTR-897 19 nt Target #2: 5′-GCAAGCAAAGCACGUAUUA-3′(SEQ ID NO: 3052) TTR-897 19 nt Target #3: 5′-UGCAAGCAAAGCACGUAUU-3′(SEQ ID NO: 3436) TTR-898 19 nt Target #1: 5′-AAGCAAAGCACGUAUUAAA-3′(SEQ ID NO: 2669) TTR-898 19 nt Target #2: 5′-CAAGCAAAGCACGUAUUAA-3′(SEQ ID NO: 3053) TTR-898 19 nt Target #3: 5′-GCAAGCAAAGCACGUAUUA-3′(SEQ ID NO: 3437) TTR-899 19 nt Target #1: 5′-AGCAAAGCACGUAUUAAAU-3′(SEQ ID NO: 2670) TTR-899 19 nt Target #2: 5′-AAGCAAAGCACGUAUUAAA-3′(SEQ ID NO: 3054) TTR-899 19 nt Target #3: 5′-CAAGCAAAGCACGUAUUAA-3′(SEQ ID NO: 3438) TTR-900 19 nt Target #1: 5′-GCAAAGCACGUAUUAAAUA-3′(SEQ ID NO: 2671) TTR-900 19 nt Target #2: 5′-AGCAAAGCACGUAUUAAAU-3′(SEQ ID NO: 3055) TTR-900 19 nt Target #3: 5′-AAGCAAAGCACGUAUUAAA-3′(SEQ ID NO: 3439) TTR-901 19 nt Target #1: 5′-CAAAGCACGUAUUAAAUAU-3′(SEQ ID NO: 2672) TTR-901 19 nt Target #2: 5′-GCAAAGCACGUAUUAAAUA-3′(SEQ ID NO: 3056) TTR-901 19 nt Target #3: 5′-AGCAAAGCACGUAUUAAAU-3′(SEQ ID NO: 3440) TTR-902 19 nt Target #1: 5′-AAAGCACGUAUUAAAUAUG-3′(SEQ ID NO: 2673) TTR-902 19 nt Target #2: 5′-CAAAGCACGUAUUAAAUAU-3′(SEQ ID NO: 3057) TTR-902 19 nt Target #3: 5′-GCAAAGCACGUAUUAAAUA-3′(SEQ ID NO: 3441) TTR-903 19 nt Target #1: 5′-AAGCACGUAUUAAAUAUGA-3′(SEQ ID NO: 2674) TTR-903 19 nt Target #2: 5′-AAAGCACGUAUUAAAUAUG-3′(SEQ ID NO: 3058) TTR-903 19 nt Target #3: 5′-CAAAGCACGUAUUAAAUAU-3′(SEQ ID NO: 3442) TTR-904 19 nt Target #1: 5′-AGCACGUAUUAAAUAUGAU-3′(SEQ ID NO: 2675) TTR-904 19 nt Target #2: 5′-AAGCACGUAUUAAAUAUGA-3′(SEQ ID NO: 3059) TTR-904 19 nt Target #3: 5′-AAAGCACGUAUUAAAUAUG-3′(SEQ ID NO: 3443) TTR-905 19 nt Target #1: 5′-GCACGUAUUAAAUAUGAUC-3′(SEQ ID NO: 2676) TTR-905 19 nt Target #2: 5′-AGCACGUAUUAAAUAUGAU-3′(SEQ ID NO: 3060) TTR-905 19 nt Target #3: 5′-AAGCACGUAUUAAAUAUGA-3′(SEQ ID NO: 3444) TTR-906 19 nt Target #1: 5′-CACGUAUUAAAUAUGAUCU-3′(SEQ ID NO: 2677) TTR-906 19 nt Target #2: 5′-GCACGUAUUAAAUAUGAUC-3′(SEQ ID NO: 3061) TTR-906 19 nt Target #3: 5′-AGCACGUAUUAAAUAUGAU-3′(SEQ ID NO: 3445) TTR-908 19 nt Target #1: 5′-CGUAUUAAAUAUGAUCUGC-3′(SEQ ID NO: 2678) TTR-908 19 nt Target #2: 5′-ACGUAUUAAAUAUGAUCUG-3′(SEQ ID NO: 3062) TTR-908 19 nt Target #3: 5′-CACGUAUUAAAUAUGAUCU-3′(SEQ ID NO: 3446) TTR-909 19 nt Target #1: 5′-GUAUUAAAUAUGAUCUGCA-3′(SEQ ID NO: 2679) TTR-909 19 nt Target #2: 5′-CGUAUUAAAUAUGAUCUGC-3′(SEQ ID NO: 3063) TTR-909 19 nt Target #3: 5′-ACGUAUUAAAUAUGAUCUG-3′(SEQ ID NO: 3447) TTR-911 19 nt Target #1: 5′-AUUAAAUAUGAUCUGCAGC-3′(SEQ ID NO: 2680) TTR-911 19 nt Target #2: 5′-UAUUAAAUAUGAUCUGCAG-3′(SEQ ID NO: 3064) TTR-911 19 nt Target #3: 5′-GUAUUAAAUAUGAUCUGCA-3′(SEQ ID NO: 3448) TTR-912 19 nt Target #1: 5′-UUAAAUAUGAUCUGCAGCC-3′(SEQ ID NO: 2681) TTR-912 19 nt Target #2: 5′-AUUAAAUAUGAUCUGCAGC-3′(SEQ ID NO: 3065) TTR-912 19 nt Target #3: 5′-UAUUAAAUAUGAUCUGCAG-3′(SEQ ID NO: 3449) TTR-913 19 nt Target #1: 5′-UAAAUAUGAUCUGCAGCCA-3′(SEQ ID NO: 2682) TTR-913 19 nt Target #2: 5′-UUAAAUAUGAUCUGCAGCC-3′(SEQ ID NO: 3066) TTR-913 19 nt Target #3: 5′-AUUAAAUAUGAUCUGCAGC-3′(SEQ ID NO: 3450) TTR-914 19 nt Target #1: 5′-AAAUAUGAUCUGCAGCCAU-3′(SEQ ID NO: 2683) TTR-914 19 nt Target #2: 5′-UAAAUAUGAUCUGCAGCCA-3′(SEQ ID NO: 3067) TTR-914 19 nt Target #3: 5′-UUAAAUAUGAUCUGCAGCC-3′(SEQ ID NO: 3451) TTR-915 19 nt Target #1: 5′-AAUAUGAUCUGCAGCCAUU-3′(SEQ ID NO: 2684) TTR-915 19 nt Target #2: 5′-AAAUAUGAUCUGCAGCCAU-3′(SEQ ID NO: 3068) TTR-915 19 nt Target #3: 5′-UAAAUAUGAUCUGCAGCCA-3′(SEQ ID NO: 3452) TTR-916 19 nt Target #1: 5′-AUAUGAUCUGCAGCCAUUA-3′(SEQ ID NO: 2685) TTR-916 19 nt Target #2: 5′-AAUAUGAUCUGCAGCCAUU-3′(SEQ ID NO: 3069) TTR-916 19 nt Target #3: 5′-AAAUAUGAUCUGCAGCCAU-3′(SEQ ID NO: 3453) TTR-917 19 nt Target #1: 5′-UAUGAUCUGCAGCCAUUAA-3′(SEQ ID NO: 2686) TTR-917 19 nt Target #2: 5′-AUAUGAUCUGCAGCCAUUA-3′(SEQ ID NO: 3070) TTR-917 19 nt Target #3: 5′-AAUAUGAUCUGCAGCCAUU-3′(SEQ ID NO: 3454) TTR-918 19 nt Target #1: 5′-AUGAUCUGCAGCCAUUAAA-3′(SEQ ID NO: 2687) TTR-918 19 nt Target #2: 5′-UAUGAUCUGCAGCCAUUAA-3′(SEQ ID NO: 3071) TTR-918 19 nt Target #3: 5′-AUAUGAUCUGCAGCCAUUA-3′(SEQ ID NO: 3455) TTR-919 19 nt Target #1: 5′-UGAUCUGCAGCCAUUAAAA-3′(SEQ ID NO: 2688) TTR-919 19 nt Target #2: 5′-AUGAUCUGCAGCCAUUAAA-3′(SEQ ID NO: 3072) TTR-919 19 nt Target #3: 5′-UAUGAUCUGCAGCCAUUAA-3′(SEQ ID NO: 3456)

Within Tables 2, 3 and 5 above, underlined residues indicate 2-O-methylresidues, UPPER CASE indicates ribonucleotides, and lower case denotesdeoxyribonucleotides. The DsiRNA agents of Tables 2 and 3 above are25/27 mer agents possessing a blunt end. The structures and/ormodification patterning of the agents of Tables 2 and 3 above can bereadily adapted to the above generic sequence structures, e.g., the 3′overhang of the second strand can be extended or contracted,2-O-methylation of the second strand can be expanded towards the 5′ endof the second strand, optionally at alternating sites, etc. Such furthermodifications are optional, as 25/27 mer DsiRNAs with such modificationscan also be readily designed from the above DsiRNA agents and are alsoexpected to be functional inhibitors of transthyretin expression.Similarly, the 27 mer “blunt/blunt” DsiRNA structures and/ormodification patterns of the agents of Table 5 above can also be readilyadapted to the above generic sequence structures, e.g., for applicationof modification patterning of the antisense strand to such structuresand/or adaptation of such sequences to the above generic structures.

In certain embodiments, 27 mer DsiRNAs possessing independent strandlengths each of 27 nucleotides are designed and synthesized fortargeting of the same sites within the transthyretin transcript as theasymmetric “25/27” structures shown in Tables 2 and 3 herein. Exemplary“27/27” DsiRNAs are optionally designed with a “blunt/blunt” structureas shown for the DsiRNAs of Table 5 above.

In certain embodiments, the dsRNA agents of the invention require, e.g.,at least 19, at least 20, at least 21, at least 22, at least 23, atleast 24, at least 25 or at least 26 residues of the first strand to becomplementary to corresponding residues of the second strand. In certainrelated embodiments, these first strand residues complementary tocorresponding residues of the second strand are optionally consecutiveresidues.

As used herein “DsiRNAmm” refers to a DisRNA having a “mismatch tolerantregion” containing one, two, three or four mismatched base pairs of theduplex formed by the sense and antisense strands of the DsiRNA, wheresuch mismatches are positioned within the DsiRNA at a location(s) lyingbetween (and thus not including) the two terminal base pairs of eitherend of the DsiRNA. The mismatched base pairs are located within a“mismatch-tolerant region” which is defined herein with respect to thelocation of the projected Ago2 cut site of the corresponding targetnucleic acid. The mismatch tolerant region is located “upstream of” theprojected Ago2 cut site of the target strand. “Upstream” in this contextwill be understood as the 5′-most portion of the DsiRNAmm duplex, where5′ refers to the orientation of the sense strand of the DsiRNA duplex.Therefore, the mismatch tolerant region is upstream of the base on thesense (passenger) strand that corresponds to the projected Ago2 cut siteof the target nucleic acid (see FIG. 1); alternatively, when referringto the antisense (guide) strand of the DsiRNAmm, the mismatch tolerantregion can also be described as positioned downstream of the base thatis complementary to the projected Ago2 cut site of the target nucleicacid, that is, the 3′-most portion of the antisense strand of theDsiRNAmm (where position 1 of the antisense strand is the 5′ terminalnucleotide of the antisense strand, see FIG. 1).

In one embodiment, for example with numbering as depicted in FIG. 1, themismatch tolerant region is positioned between and including base pairs3-9 when numbered from the nucleotide starting at the 5′ end of thesense strand of the duplex. Therefore, a DsiRNAmm of the inventionpossesses a single mismatched base pair at any one of positions 3, 4, 5,6, 7, 8 or 9 of the sense strand of a right-hand extended DsiRNA (whereposition 1 is the 5′ terminal nucleotide of the sense strand andposition 9 is the nucleotide residue of the sense strand that isimmediately 5′ of the projected Ago2 cut site of the targettransthyretin RNA sequence corresponding to the sense strand sequence).In certain embodiments, for a DsiRNAmm that possesses a mismatched basepair nucleotide at any of positions 3, 4, 5, 6, 7, 8 or 9 of the sensestrand, the corresponding mismatched base pair nucleotide of theantisense strand not only forms a mismatched base pair with the DsiRNAmmsense strand sequence, but also forms a mismatched base pair with aDsiRNAmm target transthyretin RNA sequence (thus, complementaritybetween the antisense strand sequence and the sense strand sequence isdisrupted at the mismatched base pair within the DsiRNAmm, andcomplementarity is similarly disrupted between the antisense strandsequence of the DsiRNAmm and the target transthyretin RNA sequence). Inalternative embodiments, the mismatch base pair nucleotide of theantisense strand of a DsiRNAmm only form a mismatched base pair with acorresponding nucleotide of the sense strand sequence of the DsiRNAmm,yet base pairs with its corresponding target transthyretin RNA sequencenucleotide (thus, complementarity between the antisense strand sequenceand the sense strand sequence is disrupted at the mismatched base pairwithin the DsiRNAmm, yet complementarity is maintained between theantisense strand sequence of the DsiRNAmm and the target transthyretinRNA sequence).

A DsiRNAmm of the invention that possesses a single mismatched base pairwithin the mismatch-tolerant region (mismatch region) as described above(e.g., a DsiRNAmm harboring a mismatched nucleotide residue at any oneof positions 3, 4, 5, 6, 7, 8 or 9 of the sense strand) can furtherinclude one, two or even three additional mismatched base pairs. Inpreferred embodiments, these one, two or three additional mismatchedbase pairs of the DsiRNAmm occur at position(s) 3, 4, 5, 6, 7, 8 and/or9 of the sense strand (and at corresponding residues of the antisensestrand). In one embodiment where one additional mismatched base pair ispresent within a DsiRNAmm, the two mismatched base pairs of the sensestrand can occur, e.g., at nucleotides of both position 4 and position 6of the sense strand (with mismatch also occurring at correspondingnucleotide residues of the antisense strand).

In DsiRNAmm agents possessing two mismatched base pairs, mismatches canoccur consecutively (e.g., at consecutive positions along the sensestrand nucleotide sequence). Alternatively, nucleotides of the sensestrand that form mismatched base pairs with the antisense strandsequence can be interspersed by nucleotides that base pair with theantisense strand sequence (e.g., for a DsiRNAmm possessing mismatchednucleotides at positions 3 and 6, but not at positions 4 and 5, themismatched residues of sense strand positions 3 and 6 are interspersedby two nucleotides that form matched base pairs with correspondingresidues of the antisense strand). For example, two residues of thesense strand (located within the mismatch-tolerant region of the sensestrand) that form mismatched base pairs with the corresponding antisensestrand sequence can occur with zero, one, two, three, four or fivematched base pairs located between these mismatched base pairs.

For certain DsiRNAmm agents possessing three mismatched base pairs,mismatches can occur consecutively (e.g., in a triplet along the sensestrand nucleotide sequence). Alternatively, nucleotides of the sensestrand that form mismatched base pairs with the antisense strandsequence can be interspersed by nucleotides that form matched base pairswith the antisense strand sequence (e.g., for a DsiRNAmm possessingmismatched nucleotides at positions 3, 4 and 8, but not at positions 5,6 and 7, the mismatched residues of sense strand positions 3 and 4 areadjacent to one another, while the mismatched residues of sense strandpositions 4 and 8 are interspersed by three nucleotides that formmatched base pairs with corresponding residues of the antisense strand).For example, three residues of the sense strand (located within themismatch-tolerant region of the sense strand) that form mismatched basepairs with the corresponding antisense strand sequence can occur withzero, one, two, three or four matched base pairs located between any twoof these mismatched base pairs.

For certain DsiRNAmm agents possessing four mismatched base pairs,mismatches can occur consecutively (e.g., in a quadruplet along thesense strand nucleotide sequence). Alternatively, nucleotides of thesense strand that form mismatched base pairs with the antisense strandsequence can be interspersed by nucleotides that form matched base pairswith the antisense strand sequence (e.g., for a DsiRNAmm possessingmismatched nucleotides at positions 3, 5, 7 and 8, but not at positions4 and 6, the mismatched residues of sense strand positions 7 and 8 areadjacent to one another, while the mismatched residues of sense strandpositions 3 and 5 are interspersed by one nucleotide that forms amatched base pair with the corresponding residue of the antisensestrand—similarly, the the mismatched residues of sense strand positions5 and 7 are also interspersed by one nucleotide that forms a matchedbase pair with the corresponding residue of the antisense strand). Forexample, four residues of the sense strand (located within themismatch-tolerant region of the sense strand) that form mismatched basepairs with the corresponding antisense strand sequence can occur withzero, one, two or three matched base pairs located between any two ofthese mismatched base pairs.

In another embodiment, for example with numbering also as depicted inFIG. 1, a DsiRNAmm of the invention comprises a mismatch tolerant regionwhich possesses a single mismatched base pair nucleotide at any one ofpositions 17, 18, 19, 20, 21, 22 or 23 of the antisense strand of theDsiRNA (where position 1 is the 5′ terminal nucleotide of the antisensestrand and position 17 is the nucleotide residue of the antisense strandthat is immediately 3′ (downstream) in the antisense strand of theprojected Ago2 cut site of the target transthyretin RNA sequencesufficiently complementary to the antisense strand sequence). In certainembodiments, for a DsiRNAmm that possesses a mismatched base pairnucleotide at any of positions 17, 18, 19, 20, 21, 22 or 23 of theantisense strand with respect to the sense strand of the DsiRNAmm, themismatched base pair nucleotide of the antisense strand not only forms amismatched base pair with the DsiRNAmm sense strand sequence, but alsoforms a mismatched base pair with a DsiRNAmm target transthyretin RNAsequence (thus, complementarity between the antisense strand sequenceand the sense strand sequence is disrupted at the mismatched base pairwithin the DsiRNAmm, and complementarity is similarly disrupted betweenthe antisense strand sequence of the DsiRNAmm and the targettransthyretin RNA sequence). In alternative embodiments, the mismatchbase pair nucleotide of the antisense strand of a DsiRNAmm only forms amismatched base pair with a corresponding nucleotide of the sense strandsequence of the DsiRNAmm, yet base pairs with its corresponding targettransthyretin RNA sequence nucleotide (thus, complementarity between theantisense strand sequence and the sense strand sequence is disrupted atthe mismatched base pair within the DsiRNAmm, yet complementarity ismaintained between the antisense strand sequence of the DsiRNAmm and thetarget transthyretin RNA sequence).

A DsiRNAmm of the invention that possesses a single mismatched base pairwithin the mismatch-tolerant region as described above (e.g., a DsiRNAmmharboring a mismatched nucleotide residue at positions 17, 18, 19, 20,21, 22 or 23 of the antisense strand) can further include one, two oreven three additional mismatched base pairs. In preferred embodiments,these one, two or three additional mismatched base pairs of the DsiRNAmmoccur at position(s) 17, 18, 19, 20, 21, 22 and/or 23 of the antisensestrand (and at corresponding residues of the sense strand). In oneembodiment where one additional mismatched base pair is present within aDsiRNAmm, the two mismatched base pairs of the antisense strand canoccur, e.g., at nucleotides of both position 18 and position 20 of theantisense strand (with mismatch also occurring at correspondingnucleotide residues of the sense strand).

In DsiRNAmm agents possessing two mismatched base pairs, mismatches canoccur consecutively (e.g., at consecutive positions along the antisensestrand nucleotide sequence). Alternatively, nucleotides of the antisensestrand that form mismatched base pairs with the sense strand sequencecan be interspersed by nucleotides that base pair with the sense strandsequence (e.g., for a DsiRNAmm possessing mismatched nucleotides atpositions 17 and 20, but not at positions 18 and 19, the mismatchedresidues of antisense strand positions 17 and 20 are interspersed by twonucleotides that form matched base pairs with corresponding residues ofthe sense strand). For example, two residues of the antisense strand(located within the mismatch-tolerant region of the sense strand) thatform mismatched base pairs with the corresponding sense strand sequencecan occur with zero, one, two, three, four, five, six or seven matchedbase pairs located between these mismatched base pairs.

For certain DsiRNAmm agents possessing three mismatched base pairs,mismatches can occur consecutively (e.g., in a triplet along theantisense strand nucleotide sequence). Alternatively, nucleotides of theantisense strand that form mismatched base pairs with the sense strandsequence can be interspersed by nucleotides that form matched base pairswith the sense strand sequence (e.g., for a DsiRNAmm possessingmismatched nucleotides at positions 17, 18 and 22, but not at positions19, 20 and 21, the mismatched residues of antisense strand positions 17and 18 are adjacent to one another, while the mismatched residues ofantisense strand positions 18 and 122 are interspersed by threenucleotides that form matched base pairs with corresponding residues ofthe sense strand). For example, three residues of the antisense strand(located within the mismatch-tolerant region of the antisense strand)that form mismatched base pairs with the corresponding sense strandsequence can occur with zero, one, two, three, four, five or six matchedbase pairs located between any two of these mismatched base pairs.

For certain DsiRNAmm agents possessing four mismatched base pairs,mismatches can occur consecutively (e.g., in a quadruplet along theantisense strand nucleotide sequence). Alternatively, nucleotides of theantisense strand that form mismatched base pairs with the sense strandsequence can be interspersed by nucleotides that form matched base pairswith the sense strand sequence (e.g., for a DsiRNAmm possessingmismatched nucleotides at positions 18, 20, 22 and 23, but not atpositions 19 and 21, the mismatched residues of antisense strandpositions 22 and 23 are adjacent to one another, while the mismatchedresidues of antisense strand positions 18 and 20 are interspersed by onenucleotide that forms a matched base pair with the corresponding residueof the sense strand—similarly, the the mismatched residues of antisensestrand positions 20 and 22 are also interspersed by one nucleotide thatforms a matched base pair with the corresponding residue of the sensestrand). For example, four residues of the antisense strand (locatedwithin the mismatch-tolerant region of the antisense strand) that formmismatched base pairs with the corresponding sense strand sequence canoccur with zero, one, two, three, four or five matched base pairslocated between any two of these mismatched base pairs.

For reasons of clarity, the location(s) of mismatched nucleotideresidues within the above DsiRNAmm agents are numbered in reference tothe 5′ terminal residue of either sense or antisense strands of theDsiRNAmm. The numbering of positions located within themismatch-tolerant region (mismatch region) of the antisense strand canshift with variations in the proximity of the 5′ terminus of the senseor antisense strand to the projected Ago2 cleavage site. Thus, thelocation(s) of preferred mismatch sites within either antisense strandor sense strand can also be identified as the permissible proximity ofsuch mismatches to the projected Ago2 cut site. Accordingly, in onepreferred embodiment, the position of a mismatch nucleotide of the sensestrand of a DsiRNAmm is the nucleotide residue of the sense strand thatis located immediately 5′ (upstream) of the projected Ago2 cleavage siteof the corresponding target transthyretin RNA sequence. In otherpreferred embodiments, a mismatch nucleotide of the sense strand of aDsiRNAmm is positioned at the nucleotide residue of the sense strandthat is located two nucleotides 5′ (upstream) of the projected Ago2cleavage site, three nucleotides 5′ (upstream) of the projected Ago2cleavage site, four nucleotides 5′ (upstream) of the projected Ago2cleavage site, five nucleotides 5′ (upstream) of the projected Ago2cleavage site, six nucleotides 5′ (upstream) of the projected Ago2cleavage site, seven nucleotides 5′ (upstream) of the projected Ago2cleavage site, eight nucleotides 5′ (upstream) of the projected Ago2cleavage site, or nine nucleotides 5′ (upstream) of the projected Ago2cleavage site.

Exemplary single mismatch-containing 25/27 mer DsiRNAs (DsiRNAmm)include the following structures (such mismatch-containing structuresmay also be incorporated into other exemplary DsiRNA structures shownherein).

  5′-XX^(M)XXXXXXXXXXXXXXXXXXXXDD-3′3′-XXXX_(M)XXXXXXXXXXXXXXXXXXXXXX-5′  5′-XXX^(M)XXXXXXXXXXXXXXXXXXXDD-3′3′-XXXXX_(M)XXXXXXXXXXXXXXXXXXXXX-5′  5′-XXXX^(M)XXXXXXXXXXXXXXXXXXDD-3′3′-XXXXXX_(M)XXXXXXXXXXXXXXXXXXXX-5′  5′-XXXXX^(M)XXXXXXXXXXXXXXXXXDD-3′3′-XXXXXXX_(M)XXXXXXXXXXXXXXXXXXX-5′  5′-XXXXXX^(M)XXXXXXXXXXXXXXXXDD-3′3′-XXXXXXXX_(M)XXXXXXXXXXXXXXXXXX-5′  5′-XXXXXXX^(M)XXXXXXXXXXXXXXXDD-3′3′-XXXXXXXXX_(M)XXXXXXXXXXXXXXXXX-5′  5′-XXXXXXXX^(M)XXXXXXXXXXXXXXDD-3′3′-XXXXXXXXXX_(M)XXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “D”=DNA and “M”=Nucleic acid residues (RNA, DNA ornon-natural or modified nucleic acids) that do not base pair (hydrogenbond) with corresponding “M” residues of otherwise complementary strandwhen strands are annealed. Any of the residues of such agents canoptionally be 2′-O-methyl RNA monomers—alternating positioning of2′-O-methyl RNA monomers that commences from the 3′-terminal residue ofthe bottom (second) strand, as shown above, can also be used in theabove DsiRNAmm agents. For the above mismatch structures, the top strandis the sense strand, and the bottom strand is the antisense strand.

In certain embodiments, a DsiRNA of the invention can contain mismatchesthat exist in reference to the target transthyretin RNA sequence yet donot necessarily exist as mismatched base pairs within the two strands ofthe DsiRNA—thus, a DsiRNA can possess perfect complementarity betweenfirst and second strands of a DsiRNA, yet still possess mismatchedresidues in reference to a target transthyretin RNA (which, in certainembodiments, may be advantageous in promoting efficacy and/or potencyand/or duration of effect). In certain embodiments, where mismatchesoccur between antisense strand and target transthyretin RNA sequence,the position of a mismatch is located within the antisense strand at aposition(s) that corresponds to a sequence of the sense strand located5′ of the projected Ago2 cut site of the target region—e.g., antisensestrand residue(s) positioned within the antisense strand to the 3′ ofthe antisense residue which is complementary to the projected Ago2 cutsite of the target sequence.

Exemplary 25/27 mer DsiRNAs that harbor a single mismatched residue inreference to target sequences include the following structures.

Target RNA Sequence: 5′-...AXXXXXXXXXXXXXXXXXXXX...-3′DsiRNAmm Sense Strand:   5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′DsiRNAmm Antisense Strand: 3′-EXXXXXXXXXXXXXXXXXXXXXXXXXX-5′Target RNA Sequence: 5′-...XAXXXXXXXXXXXXXXXXXXX...-3′DsiRNAmm Sense Strand:   5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′DsiRNAmm Antisense Strand: 3′-XEXXXXXXXXXXXXXXXXXXXXXXXXX-5′Target RNA Sequence:   5′-...AXXXXXXXXXXXXXXXXXX...-3′DsiRNAmm Sense Strand:   5′-BXXXXXXXXXXXXXXXXXXXXXXDD-3′DsiRNAmm Antisense Strand: 3′-XXEXXXXXXXXXXXXXXXXXXXXXXXX-5′Target RNA Sequence:   5′-...XAXXXXXXXXXXXXXXXXX...-3′DsiRNAmm Sense Strand:   5′-XBXXXXXXXXXXXXXXXXXXXXXDD-3′DsiRNAmm Antisense Strand: 3′-XXXEXXXXXXXXXXXXXXXXXXXXXXX-5′Target RNA Sequence:   5′-...XXAXXXXXXXXXXXXXXXX...-3′DsiRNAmm Sense Strand:   5′-XXBXXXXXXXXXXXXXXXXXXXXDD-3′DsiRNAmm Antisense Strand: 3′-XXXXEXXXXXXXXXXXXXXXXXXXXXX-5′Target RNA Sequence:   5′-...XXXAXXXXXXXXXXXXXXX...-3′DsiRNAmm Sense Strand:   5′-XXXBXXXXXXXXXXXXXXXXXXXDD-3′DsiRNAmm Antisense Strand: 3′-XXXXXEXXXXXXXXXXXXXXXXXXXXX-5′Target RNA Sequence:   5′-...XXXXAXXXXXXXXXXXXXX...-3′DsiRNAmm Sense Strand:   5′-XXXXBXXXXXXXXXXXXXXXXXXDD-3′DsiRNAmm Antisense Strand: 3′-XXXXXXEXXXXXXXXXXXXXXXXXXXX-5′Target RNA Sequence:   5′-...XXXXXAXXXXXXXXXXXXX...-3′DsiRNAmm Sense Strand:   5′-XXXXXBXXXXXXXXXXXXXXXXXDD-3′DsiRNAmm Antisense Strand: 3′-XXXXXXXEXXXXXXXXXXXXXXXXXXX-5′Target RNA Sequence:   5′-...XXXXXXAXXXXXXXXXXXX...-3′DsiRNAmm Sense Strand:   5′-XXXXXXBXXXXXXXXXXXXXXXXDD-3′DsiRNAmm Antisense Strand: 3′-XXXXXXXXEXXXXXXXXXXXXXXXXXX-5′Target RNA Sequence:   5′-...XXXXXXXAXXXXXXXXXXX...-3′DsiRNAmm Sense Strand:   5′-XXXXXXXBXXXXXXXXXXXXXXXDD-3′DsiRNAmm Antisense Strand: 3′-XXXXXXXXXEXXXXXXXXXXXXXXXXX-5′Target RNA Sequence:   5′-...XXXXXXXXAXXXXXXXXXX...-3′DsiRNAmm Sense Strand:   5′-XXXXXXXXBXXXXXXXXXXXXXXDD-3′DsiRNAmm Antisense Strand: 3′-XXXXXXXXXXEXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “D”=DNA and “E”=Nucleic acid residues (RNA, DNA ornon-natural or modified nucleic acids) that do not base pair (hydrogenbond) with corresponding “A” RNA residues of otherwise complementary(target) strand when strands are annealed, yet optionally do base pairwith corresponding “B” residues (“B” residues are also RNA, DNA ornon-natural or modified nucleic acids). Any of the residues of suchagents can optionally be 2′-O-methyl RNA monomers—alternatingpositioning of 2′-O-methyl RNA monomers that commences from the3′-terminal residue of the bottom (second) strand, as shown above, canalso be used in the above DsiRNA agents.

In certain embodiments, the guide strand of a dsRNA of the inventionthat is sufficiently complementary to a target RNA (e.g., mRNA) along atleast 19 nucleotides of the target gene sequence to reduce target geneexpression is not perfectly complementary to the at least 19 nucleotidelong target gene sequence. Rather, it is appreciated that the guidestrand of a dsRNA of the invention that is sufficiently complementary toa target mRNA along at least 19 nucleotides of a target RNA sequence toreduce target gene expression can have one, two, three, or even four ormore nucleotides that are mismatched with the 19 nucleotide or longertarget strand sequence. Thus, for a 19 nucleotide target RNA sequence,the guide strand of a dsRNA of the invention can be sufficientlycomplementary to the target RNA sequence to reduce target gene levelswhile possessing, e.g., only 15/19, 16/19, 17/19 or 18/19 matchednucleotide residues between guide strand and target RNA sequence.

In addition to the above-exemplified structures, dsRNAs of the inventioncan also possess one, two or three additional residues that form furthermismatches with the target transthyretin RNA sequence. Such mismatchescan be consecutive, or can be interspersed by nucleotides that formmatched base pairs with the target transthyretin RNA sequence. Whereinterspersed by nucleotides that form matched base pairs, mismatchedresidues can be spaced apart from each other within a single strand atan interval of one, two, three, four, five, six, seven or even eightbase paired nucleotides between such mismatch-forming residues.

As for the above-described DsiRNAmm agents, a preferred location withindsRNAs (e.g., DsiRNAs) for antisense strand nucleotides that formmismatched base pairs with target transthyretin RNA sequence (yet may ormay not form mismatches with corresponding sense strand nucleotides) iswithin the antisense strand region that is located 3′ (downstream) ofthe antisense strand sequence which is complementary to the projectedAgo2 cut site of the DsiRNA (e.g., in FIG. 1, the region of theantisense strand which is 3′ of the projected Ago2 cut site is preferredfor mismatch-forming residues and happens to be located at positions17-23 of the antisense strand for the 25/27 mer agent shown in FIG. 1).Thus, in one embodiment, the position of a mismatch nucleotide (inrelation to the target transthyretin RNA sequence) of the antisensestrand of a DsiRNAmm is the nucleotide residue of the antisense strandthat is located immediately 3′ (downstream) within the antisense strandsequence of the projected Ago2 cleavage site of the corresponding targettransthyretin RNA sequence. In other preferred embodiments, a mismatchnucleotide of the antisense strand of a DsiRNAmm (in relation to thetarget transthyretin RNA sequence) is positioned at the nucleotideresidue of the antisense strand that is located two nucleotides 3′(downstream) of the corresponding projected Ago2 cleavage site, threenucleotides 3′ (downstream) of the corresponding projected Ago2 cleavagesite, four nucleotides 3′ (downstream) of the corresponding projectedAgo2 cleavage site, five nucleotides 3′ (downstream) of thecorresponding projected Ago2 cleavage site, six nucleotides 3′(downstream) of the projected Ago2 cleavage site, seven nucleotides 3′(downstream) of the projected Ago2 cleavage site, eight nucleotides 3′(downstream) of the projected Ago2 cleavage site, or nine nucleotides 3′(downstream) of the projected Ago2 cleavage site.

In dsRNA agents possessing two mismatch-forming nucleotides of theantisense strand (where mismatch-forming nucleotides are mismatchforming in relation to target transthyretin RNA sequence), mismatchescan occur consecutively (e.g., at consecutive positions along theantisense strand nucleotide sequence). Alternatively, nucleotides of theantisense strand that form mismatched base pairs with the targettransthyretin RNA sequence can be interspersed by nucleotides that basepair with the target transthyretin RNA sequence (e.g., for a DsiRNApossessing mismatch-forming nucleotides at positions 17 and 20 (startingfrom the 5′ terminus (position 1) of the antisense strand of the 25/27mer agent shown in FIG. 1), but not at positions 18 and 19, themismatched residues of sense strand positions 17 and 20 are interspersedby two nucleotides that form matched base pairs with correspondingresidues of the target transthyretin RNA sequence). For example, tworesidues of the antisense strand (located within the mismatch-tolerantregion of the antisense strand) that form mismatched base pairs with thecorresponding target transthyretin RNA sequence can occur with zero,one, two, three, four or five matched base pairs (with respect to targettransthyretin RNA sequence) located between these mismatch-forming basepairs.

For certain dsRNAs possessing three mismatch-forming base pairs(mismatch-forming with respect to target transthyretin RNA sequence),mismatch-forming nucleotides can occur consecutively (e.g., in a tripletalong the antisense strand nucleotide sequence). Alternatively,nucleotides of the antisense strand that form mismatched base pairs withthe target transthyretin RNA sequence can be interspersed by nucleotidesthat form matched base pairs with the target transthyretin RNA sequence(e.g., for a DsiRNA possessing mismatched nucleotides at positions 17,18 and 22, but not at positions 19, 20 and 21, the mismatch-formingresidues of antisense strand positions 17 and 18 are adjacent to oneanother, while the mismatch-forming residues of antisense strandpositions 18 and 22 are interspersed by three nucleotides that formmatched base pairs with corresponding residues of the targettransthyretin RNA). For example, three residues of the antisense strand(located within the mismatch-tolerant region of the antisense strand)that form mismatched base pairs with the corresponding targettransthyretin RNA sequence can occur with zero, one, two, three or fourmatched base pairs located between any two of these mismatch-formingbase pairs.

For certain dsRNAs possessing four mismatch-forming base pairs(mismatch-forming with respect to target transthyretin RNA sequence),mismatch-forming nucleotides can occur consecutively (e.g., in aquadruplet along the sense strand nucleotide sequence). Alternatively,nucleotides of the antisense strand that form mismatched base pairs withthe target transthyretin RNA sequence can be interspersed by nucleotidesthat form matched base pairs with the target transthyretin RNA sequence(e.g., for a DsiRNA possessing mismatch-forming nucleotides at positions17, 19, 21 and 22, but not at positions 18 and 20, the mismatch-formingresidues of antisense strand positions 21 and 22 are adjacent to oneanother, while the mismatch-forming residues of antisense strandpositions 17 and 19 are interspersed by one nucleotide that forms amatched base pair with the corresponding residue of the targettransthyretin RNA sequence—similarly, the mismatch-forming residues ofantisense strand positions 19 and 21 are also interspersed by onenucleotide that forms a matched base pair with the corresponding residueof the target transthyretin RNA sequence). For example, four residues ofthe antisense strand (located within the mismatch-tolerant region of theantisense strand) that form mismatched base pairs with the correspondingtarget transthyretin RNA sequence can occur with zero, one, two or threematched base pairs located between any two of these mismatch-formingbase pairs.

The above DsiRNAmm and other dsRNA structures are described in order toexemplify certain structures of DsiRNAmm and dsRNA agents. Design of theabove DsiRNAmm and dsRNA structures can be adapted to generate, e.g.,DsiRNAmm forms of other DsiRNA structures shown infra. As exemplifiedabove, dsRNAs can also be designed that possess single mismatches (ortwo, three or four mismatches) between the antisense strand of the dsRNAand a target sequence, yet optionally can retain perfect complementaritybetween sense and antisense strand sequences of a dsRNA.

It is further noted that the dsRNA agents exemplified infra can alsopossess insertion/deletion (in/del) structures within theirdouble-stranded and/or target transthyretin RNA-aligned structures.Accordingly, the dsRNAs of the invention can be designed to possessin/del variations in, e.g., antisense strand sequence as compared totarget transthyretin RNA sequence and/or antisense strand sequence ascompared to sense strand sequence, with preferred location(s) forplacement of such in/del nucleotides corresponding to those locationsdescribed above for positioning of mismatched and/or mismatch-formingbase pairs.

It is also noted that the DsiRNAs of the instant invention can toleratemismatches within the 3-terminal region of the sense strand/5′-terminalregion of the antisense strand, as this region is modeled to beprocessed by Dicer and liberated from the guide strand sequence thatloads into RISC. Exemplary DsiRNA structures of the invention thatharbor such mismatches include the following:

Target RNA Sequence: 5′-...XXXXXXXXXXXXXXXXXXXXXHXXX...-3′DsiRNA Sense Strand:   5′-XXXXXXXXXXXXXXXXXXXXXIXDD-3′DsiRNA Antisense Strand: 3′-XXXXXXXXXXXXXXXXXXXXXXXJXXX-5′Target RNA Sequence: 5′-...XXXXXXXXXXXXXXXXXXXXXXHXX...-3′DsiRNA Sense Strand:   5′-XXXXXXXXXXXXXXXXXXXXXXIDD-3′DsiRNA Antisense Strand: 3′-XXXXXXXXXXXXXXXXXXXXXXXXJXX-5′Target RNA Sequence: 5′-...XXXXXXXXXXXXXXXXXXXXXXXHX...-3′DsiRNA Sense Strand:   5′-XXXXXXXXXXXXXXXXXXXXXXXID-3′DsiRNA Antisense Strand: 3′-XXXXXXXXXXXXXXXXXXXXXXXXXJX-5′Target RNA Sequence: 5′-...XXXXXXXXXXXXXXXXXXXXXXXXH...-3′DsiRNA Sense Strand:   5′-XXXXXXXXXXXXXXXXXXXXXXXDI-3′DsiRNA Antisense Strand: 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXJ-5′wherein “X”=RNA, “D”=DNA and “I” and “J”=Nucleic acid residues (RNA, DNAor non-natural or modified nucleic acids) that do not base pair(hydrogen bond) with one another, yet optionally “J” is complementary totarget RNA sequence nucleotide “H”. Any of the residues of such agentscan optionally be 2′-O-methyl RNA monomers—alternating positioning of2′-O-methyl RNA monomers that commences from the 3-terminal residue ofthe bottom (second) strand, as shown above—or any of the above-describedmethylation patterns—can also be used in the above DsiRNA agents. Theabove mismatches can also be combined within the DsiRNAs of the instantinvention.

In the below exemplary structures, such mismatches are introduced withinthe asymmetric TTR-242 DsiRNA (newly-introduced mismatch residues areitalicized): TTR-242 25/27 Mer DsiRNA, Mismatch Position=19 of SenseStrand (from 5′-Terminus)

(SEQ ID NO: 3460) 5′-UCCAAGUGUCCUCUGAU

UCAAag-3′ (SEQ ID NO: 443) 3′-UUAGGUUCACAGGAGACUA

AGUUUC-5′Optionally, the mismatched ‘A’ residue of position 19 of the sensestrand is alternatively ‘U’ or ‘C’.TTR-242 25/27 Mer DsiRNA, Mismatch Position=20 of Sense Strand (from5′-Terminus)

(SEQ ID NO: 3461) 5′-UCCAAGUGUCCUCUGAUG

CAAag-3′ (SEQ ID NO: 443) 3′-UUAGGUUCACAGGAGACUAC

GUUUC-5′Optionally, the mismatched ‘A’ residue of position 20 of the sensestrand is alternatively ‘C’ or ‘G’.TTR-242 25/27 Mer DsiRNA, Mismatch Position=21 of Sense Strand (from5′-Terminus)

(SEQ ID NO: 3462) 5′-UCCAAGUGUCCUCUGAUGG

AAag-3′ (SEQ ID NO: 443) 3′-UUAGGUUCACAGGAGACUACC

UUUC-5′Optionally, the mismatched ‘A’ residue of position 21 of the sensestrand is alternatively ‘U’ or ‘G’.TTR-242 25/27 Mer DsiRNA, Mismatch Position=22 of Sense Strand (from5′-Terminus)

(SEQ ID NO: 3463) 5′-UCCAAGUGUCCUCUGAUGGU

Aag-3′ (SEQ ID NO: 443) 3′-UUAGGUUCACAGGAGACUACCA

UUC-5′Optionally, the mismatched ‘G’ residue of position 22 of the sensestrand is alternatively ‘U’ or ‘C’.TTR-242 25/27 Mer DsiRNA, Mismatch Position=23 of Sense Strand (from5′-Terminus)

(SEQ ID NO: 3464) 5′-UCCAAGUGUCCUCUGAUGGUC

ag-3′ (SEQ ID NO: 443) 3′-UUAGGUUCACAGGAGACUACCAG

UC-5′Optionally, the mismatched ‘U’ residue of position 23 of the sensestrand is alternatively ‘C’ or ‘G’.TTR-242 25/27 Mer DsiRNA, Mismatch Position=24 of Sense Strand (from5′-Terminus)

(SEQ ID NO: 3465) 5′-UCCAAGUGUCCUCUGAUGGUCA

g-3′ (SEQ ID NO: 443) 3′-UUAGGUUCACAGGAGACUACCAGU

C-5′Optionally, the mismatched ‘g’ residue of position 24 of the sensestrand is alternatively ‘t’ or ‘c’.TTR-242 25/27 Mer DsiRNA, Mismatch Position=25 of Sense Strand (from5′-Terminus)

(SEQ ID NO: 3466) 5′-UCCAAGUGUCCUCUGAUGGUCAA

-3′ (SEQ ID NO: 443) 3′-UUAGGUUCACAGGAGACUACCAGUU

-5′Optionally, the mismatched ‘a’ residue of position 25 of the sensestrand is alternatively ‘t’ or ‘c’.TTR-242 25/27 Mer DsiRNA, Mismatch Position=1 of Antisense Strand (from5′-Terminus)

(SEQ ID NO: 59) 5′-UCCAAGUGUCCUCUGAUGGUCAA

-3′ (SEQ ID NO: 3467) 3′-UUAGGUUCACAGGAGACUACCAGUU

-5′Optionally, the mismatched ‘U’ residue of position 1 of the antisensestrand is alternatively ‘A’ or ‘G’.TTR-242 25/27 Mer DsiRNA, Mismatch Position=2 of Antisense Strand (from5′-Terminus)

(SEQ ID NO: 59) 5′-UCCAAGUGUCCUCUGAUGGUCA

g-3′ (SEQ ID NO: 3468) 3′-UUAGGUUCACAGGAGACUACCAGU

C-5′Optionally, the mismatched ‘C’ residue of position 2 of the antisensestrand is alternatively ‘A’ or ‘G’.TTR-242 25/27 Mer DsiRNA, Mismatch Position=3 of Antisense Strand (from5′-Terminus)

(SEQ ID NO: 59) 5′-UCCAAGUGUCCUCUGAUGGUC

ag-3′ (SEQ ID NO: 3469) 3′-UUAGGUUCACAGGAGACUACCAG

UC-5′Optionally, the mismatched ‘A’ residue of position 3 of the antisensestrand is alternatively ‘C’ or ‘G’.TTR-242 25/27 Mer DsiRNA, Mismatch Position=4 of Antisense Strand (from5′-Terminus)

(SEQ ID NO: 59) 5′-UCCAAGUGUCCUCUGAUGGU

Aag-3′ (SEQ ID NO: 3470) 3′-UUAGGUUCACAGGAGACUACCA

UUC-5′Optionally, the mismatched ‘C’ residue of position 4 of the antisensestrand is alternatively ‘A’ or ‘G’.TTR-242 25/27 Mer DsiRNA, Mismatch Position=5 of Antisense Strand (from5′-Terminus)

(SEQ ID NO: 59) 5′-UCCAAGUGUCCUCUGAUGG

AAag-3′ (SEQ ID NO: 3471) 3′-UUAGGUUCACAGGAGACUACC

UUUC-5′Optionally, the mismatched ‘U’ residue of position 5 of the antisensestrand is alternatively ‘A’ or ‘C’.TTR-242 25/27 Mer DsiRNA, Mismatch Position=6 of Antisense Strand (from5′-Terminus)

(SEQ ID NO: 59) 5′-UCCAAGUGUCCUCUGAUG

CAAag-3′ (SEQ ID NO: 3472) 3′-UUAGGUUCACAGGAGACUAC

GUUUC-5′Optionally, the mismatched ‘U’ residue of position 6 of the antisensestrand is alternatively ‘C’ or ‘G’.TTR-242 25/27 Mer DsiRNA, Mismatch Position=7 of Antisense Strand (from5′-Terminus)

(SEQ ID NO: 59) 5′-UCCAAGUGUCCUCUGAU

UCAAag-3′ (SEQ ID NO: 3473) 3′-UUAGGUUCACAGGAGACUA

AGUUUC-5′Optionally, the mismatched ‘U’ residue of position 7 of the antisensestrand is alternatively ‘A’ or ‘G’.

For the above oligonucleotide strand sequences, it is contemplated thatthe sense strand sequence of one depicted duplex can be combined with anantisense strand of another depicted duplex, thereby forming a distinctduplex—in certain instances, such duplexes contain a mismatched residuewith respect to the transthyretin target transcript sequence, while suchsense and antisense strand sequences do not present a mismatch at thisresidue with respect to one another (e.g., duplexes comprising SEQ IDNOs: 3466 and 3467; SEQ ID NOs: 3465 and 3468; SEQ ID NOs: 3464 and3469, etc., are contemplated as exemplary of such duplexes).

As noted above, introduction of mismatches can be performed upon any ofthe DsiRNAs described herein.

The mismatches of such DsiRNA structures can be combined to produce aDsiRNA possessing, e.g., two, three or even four mismatches within the3′-terminal four to seven nucleotides of the sense strand/5′-terminalfour to seven nucleotides of the antisense strand.

Indeed, in view of the flexibility of sequences which can beincorporated into DsiRNAs at the 3′-terminal residues of the sensestrand/5′-terminal residues of the antisense strand, in certainembodiments, the sequence requirements of an asymmetric DsiRNA of theinstant invention can be represented as the following (minimalist)structure (shown for an exemplary transthyretin-439 DsiRNA sequence):

(SEQ ID NO: 3474) 5′-AGACACCAAAUCUUACUGXXXXXX[X]_(n)-3′(SEQ ID NO: 3475) 3′-UAUCUGUGGUUUAGAAUGACXXXXXX[X]_(n)-5′where n=1 to 5, 1 to 10, 1 to 20, 1 to 30, 1 to 50, or 1 to 80 or more.transthyretin-439 mRNA Target: 5′-AUAGACACCAAAUCUUACUGXXXXXXX-3′ (SEQ IDNO: 3476).

The transthyretin target site may also be a site which is targeted byone or more of several oligonucleotides whose complementary target sitesoverlap with a stated target site. For example, for an exemplarytransthyretin-245 DsiRNA, it is noted that certain DsiRNAs targetingoverlapping and only slightly offset transthyretin sequences couldexhibit activity levels similar to that of transthyretin-245 (e.g.,transthyretin-242 to 246 of Table 2 above). Thus, in certainembodiments, a designated target sequence region might be effectivelytargeted by a series of DsiRNAs possessing largely overlappingsequences. (E.g., if considering DsiRNAs of the transthyretin-242 totransthyretin-246 target site(s), a more encompassing transthyretintranscript target sequence might be recited as, e.g.,5′-AAUCCAAGUGUCCUCUGAUGGUCAAAGUUCU-3′ (SEQ ID NO: 3477), wherein anygiven DsiRNA (e.g., a DsiRNA selected from transthyretin-238 totransthyretin-246) only targets a sub-sequence within such a sequenceregion, yet the entire sequence can be considered a viable target forsuch a series of DsiRNAs).

Additionally and/or alternatively, mismatches within the 3′-terminalseven nucleotides of the sense strand/5′-terminal seven nucleotides ofthe antisense strand can be combined with mismatches positioned at othermismatch-tolerant positions, as described above.

In view of the present identification of the above-described Dicersubstrate agents (DsiRNAs) as inhibitors of transthyretin levels viatargeting of specific transthyretin sequences, it is also recognizedthat dsRNAs having structures similar to those described herein can alsobe synthesized which target other sequences within the transthyretinsequence of NM_000371.3, or within variants thereof (e.g., targetsequences possessing 80% identity, 90% identity, 95% identity, 96%identity, 97% identity, 98% identity, 99% or more identity to a sequenceof NM_000371.3).

Anti-Transthyretin DsiRNA Design/Synthesis

It has been found empirically that longer dsRNA species of from 25 to 35nucleotides (DsiRNAs) and especially from 25 to 30 nucleotides giveunexpectedly effective results in terms of potency and duration ofaction, as compared to 19-23 mer siRNA agents. Without wishing to bebound by the underlying theory of the dsRNA processing mechanism, it isthought that the longer dsRNA species serve as a substrate for the Dicerenzyme in the cytoplasm of a cell. In addition to cleaving the dsRNA ofthe invention into shorter segments, Dicer is thought to facilitate theincorporation of a single-stranded cleavage product derived from thecleaved dsRNA into the RISC complex that is responsible for thedestruction of the cytoplasmic RNA (e.g., transthyretin RNA) of orderived from the target gene, transthyretin (or other gene associatedwith a transthyretin-associated disease or disorder). Prior studies(Rossi et al., U.S. Patent Application No. 2007/0265220) have shown thatthe cleavability of a dsRNA species (specifically, a DsiRNA agent) byDicer corresponds with increased potency and duration of action of thedsRNA species.

Certain preferred anti-transthyretin DsiRNA agents were selected from apre-screened population. Design of DsiRNAs can optionally involve use ofpredictive scoring algorithms that perform in silico assessments of theprojected activity/efficacy of a number of possible DsiRNA agentsspanning a region of sequence. Information regarding the design of suchscoring algorithms can be found, e.g., in Gong et al. (BMCBioinformatics 2006, 7:516), though a more recent “v4.3” algorithmrepresents a theoretically improved algorithm relative to siRNA scoringalgorithms previously available in the art. (E.g., “v3” and “v4” scoringalgorithms are machine learning algorithms that are not reliant upon anybiases in human sequence. In addition, the “v3” and “v4” algorithmsderive from data sets that are many-fold larger than that from which anolder “v2” algorithm such as that described in Gong et al. derives.) Thefirst and second oligonucleotides of the DsiRNA agents of the instantinvention are not required to be completely complementary. In fact, inone embodiment, the 3′-terminus of the sense strand contains one or moremismatches. In one aspect, two mismatches are incorporated at the 3′terminus of the sense strand. In another embodiment, the DsiRNA of theinvention is a double stranded RNA molecule containing two RNAoligonucleotides each of which is 27 nucleotides in length and, whenannealed to each other, have blunt ends and a two nucleotide mismatch onthe 3′-terminus of the sense strand (the 5′-terminus of the antisensestrand). The use of mismatches or decreased thermodynamic stability(specifically at the 3′-sense/5′-antisense position) has been proposedto facilitate or favor entry of the antisense strand into RISC (Schwarzet al., 2003, Cell 115: 199-208; Khvorova et al., 2003, Cell 115:209-216), presumably by affecting some rate-limiting unwinding stepsthat occur with entry of the siRNA into RISC. Thus, terminal basecomposition has been included in design algorithms for selecting active21 mer siRNA duplexes (Ui-Tei et al., 2004, Nucleic Acids Res 32:936-948; Reynolds et al., 2004, Nat Biotechnol 22: 326-330). With Dicercleavage of the dsRNA of this embodiment, the small end-terminalsequence which contains the mismatches will either be left unpaired withthe antisense strand (become part of a 3′-overhang) or be cleavedentirely off the final 21-mer siRNA. These “mismatches”, therefore, donot persist as mismatches in the final RNA component of RISC. Thefinding that base mismatches or destabilization of segments at the3′-end of the sense strand of Dicer substrate improved the potency ofsynthetic duplexes in RNAi, presumably by facilitating processing byDicer, was a surprising finding of past works describing the design anduse of 25-30 mer dsRNAs (also termed “DsiRNAs” herein; Rossi et al.,U.S. Patent Application Nos. 2005/0277610, 2005/0244858 and2007/0265220).

Modification of Anti-Transthyretin dsRNAs

One major factor that inhibits the effect of double stranded RNAs(“dsRNAs”) is the degradation of dsRNAs (e.g., siRNAs and DsiRNAs) bynucleases. A 3′-exonuclease is the primary nuclease activity present inserum and modification of the 3′-ends of antisense DNA oligonucleotidesis crucial to prevent degradation (Eder et al., 1991, Antisense Res Dev,1: 141-151). An RNase-T family nuclease has been identified called ERI-1which has 3′ to 5′ exonuclease activity that is involved in regulationand degradation of siRNAs (Kennedy et al., 2004, Nature 427: 645-649;Hong et al., 2005, Biochem J, 390: 675-679). This gene is also known asThex1 (NM_02067) in mice or THEX1 (NM_153332) in humans and is involvedin degradation of histone mRNA; it also mediates degradation of3′-overhangs in siRNAs, but does not degrade duplex RNA (Yang et al.,2006, J Biol Chem, 281: 30447-30454). It is therefore reasonable toexpect that 3′-end-stabilization of dsRNAs, including the DsiRNAs of theinstant invention, will improve stability.

XRN1 (NM_019001) is a 5′ to 3′ exonuclease that resides in P-bodies andhas been implicated in degradation of mRNA targeted by miRNA (Rehwinkelet al., 2005, RNA 11: 1640-1647) and may also be responsible forcompleting degradation initiated by internal cleavage as directed by asiRNA. XRN2 (NM_012255) is a distinct 5′ to 3′ exonuclease that isinvolved in nuclear RNA processing.

RNase A is a major endonuclease activity in mammals that degrades RNAs.It is specific for ssRNA and cleaves at the 3′-end of pyrimidine bases.SiRNA degradation products consistent with RNase A cleavage can bedetected by mass spectrometry after incubation in serum (Turner et al.,2007, Mol Biosyst 3: 43-50). The 3′-overhangs enhance the susceptibilityof siRNAs to RNase degradation. Depletion of RNase A from serum reducesdegradation of siRNAs; this degradation does show some sequencepreference and is worse for sequences having poly A/U sequence on theends (Haupenthal et al., 2006 Biochem Pharmacol 71: 702-710). Thissuggests the possibility that lower stability regions of the duplex may“breathe” and offer transient single-stranded species available fordegradation by RNase A. RNase A inhibitors can be added to serum andimprove siRNA longevity and potency (Haupenthal et al., 2007, Int J.Cancer 121: 206-210).

In 21 mers, phosphorothioate or boranophosphate modifications directlystabilize the internucleoside phosphate linkage. Boranophosphatemodified RNAs are highly nuclease resistant, potent as silencing agents,and are relatively non-toxic. Boranophosphate modified RNAs cannot bemanufactured using standard chemical synthesis methods and instead aremade by in vitro transcription (IVT) (Hall et al., 2004, Nucleic AcidsRes 32: 5991-6000; Hall et al., 2006, Nucleic Acids Res 34: 2773-2781).Phosphorothioate (PS) modifications can be easily placed in the RNAduplex at any desired position and can be made using standard chemicalsynthesis methods. The PS modification shows dose-dependent toxicity, somost investigators have recommended limited incorporation in siRNAs,favoring the 3′-ends where protection from nucleases is most important(Harborth et al., 2003, Antisense Nucleic Acid Drug Dev 13: 83-105; Chiuand Rana, 2003, Mol Cell 10: 549-561; Braasch et al., 2003, Biochemistry42: 7967-7975; Amarzguioui et al., 2003, Nucleic Acids Research 31:589-595). More extensive PS modification can be compatible with potentRNAi activity; however, use of sugar modifications (such as 2′-O-methylRNA) may be superior (Choung et al., 2006, Biochem Biophys Res Commun342: 919-927).

A variety of substitutions can be placed at the 2′-position of theribose which generally increases duplex stability (T_(m)) and cangreatly improve nuclease resistance. 2′-O-methyl RNA is a naturallyoccurring modification found in mammalian ribosomal RNAs and transferRNAs. 2′-O-methyl modification in siRNAs is known, but the preciseposition of modified bases within the duplex is important to retainpotency and complete substitution of 2′-O-methyl RNA for RNA willinactivate the siRNA. For example, a pattern that employs alternating2′-O-methyl bases can have potency equivalent to unmodified RNA and isquite stable in serum (Choung et al., 2006, Biochem Biophys Res Commun342: 919-927; Czauderna et al., 2003, Nucleic Acids Research 31:2705-2716).

The 2′-fluoro (2′-F) modification is also compatible with dsRNA (e.g.,siRNA and DsiRNA) function; it is most commonly placed at pyrimidinesites (due to reagent cost and availability) and can be combined with2′-O-methyl modification at purine positions; 2′-F purines are availableand can also be used. Heavily modified duplexes of this kind can bepotent triggers of RNAi in vitro (Allerson et al., 2005, J Med Chem 48:901-904; Prakash et al., 2005, J Med Chem 48: 4247-4253; Kraynack andBaker, 2006, RNA 12: 163-176) and can improve performance and extendduration of action when used in vivo (Morrissey et al., 2005, Hepatology41: 1349-1356; Morrissey et al., 2005, Nat Biotechnol 23: 1002-1007). Ahighly potent, nuclease stable, blunt 19 mer duplex containingalternative 2′-F and 2′-O-Me bases is taught by Allerson. In thisdesign, alternating 2′-O-Me residues are positioned in an identicalpattern to that employed by Czaudema, however the remaining RNA residuesare converted to 2′-F modified bases. A highly potent, nucleaseresistant siRNA employed by Morrissey employed a highly potent, nucleaseresistant siRNA in vivo. In addition to 2′-O-Me RNA and 2′-F RNA, thisduplex includes DNA, RNA, inverted abasic residues, and a 3′-terminal PSinternucleoside linkage. While extensive modification has certainbenefits, more limited modification of the duplex can also improve invivo performance and is both simpler and less costly to manufacture.Soutschek et al. (2004, Nature 432: 173-178) employed a duplex in vivoand was mostly RNA with two 2′-O-Me RNA bases and limited 3′-terminal PSinternucleoside linkages.

Locked nucleic acids (LNAs) are a different class of 2′-modificationthat can be used to stabilize dsRNA (e.g., siRNA and DsiRNA). Patternsof LNA incorporation that retain potency are more restricted than2′-O-methyl or 2′-F bases, so limited modification is preferred (Braaschet al., 2003, Biochemistry 42: 7967-7975; Grunweller et al., 2003,Nucleic Acids Res 31: 3185-3193; Elmen et al., 2005, Nucleic Acids Res33: 439-447). Even with limited incorporation, the use of LNAmodifications can improve dsRNA performance in vivo and may also alteror improve off target effect profiles (Mook et al., 2007, Mol CancerTher 6: 833-843).

Synthetic nucleic acids introduced into cells or live animals can berecognized as “foreign” and trigger an immune response. Immunestimulation constitutes a major class of off-target effects which candramatically change experimental results and even lead to cell death.The innate immune system includes a collection of receptor moleculesthat specifically interact with DNA and RNA that mediate theseresponses, some of which are located in the cytoplasm and some of whichreside in endosomes (Marques and Williams, 2005, Nat Biotechnol 23:1399-1405; Schlee et al., 2006, Mol Ther 14: 463-470). Delivery ofsiRNAs by cationic lipids or liposomes exposes the siRNA to bothcytoplasmic and endosomal compartments, maximizing the risk fortriggering a type 1 interferon (IFN) response both in vitro and in vivo(Morrissey et al., 2005, Nat Biotechnol 23: 1002-1007; Sioud andSorensen, 2003, Biochem Biophys Res Commun 312: 1220-1225; Sioud, 2005,J Mol Biol 348: 1079-1090; Ma et al., 2005, Biochem Biophys Res Commun330: 755-759). RNAs transcribed within the cell are less immunogenic(Robbins et al., 2006, Nat Biotechnol 24: 566-571) and synthetic RNAsthat are immunogenic when delivered using lipid-based methods can evadeimmune stimulation when introduced unto cells by mechanical means, evenin vivo (Heidel et al., 2004, Nat Biotechnol 22: 1579-1582). However,lipid based delivery methods are convenient, effective, and widely used.Some general strategy to prevent immune responses is needed, especiallyfor in vivo application where all cell types are present and the risk ofgenerating an immune response is highest. Use of chemically modifiedRNAs may solve most or even all of these problems.

In certain embodiments, modifications can be included in theanti-transthyretin dsRNA agents of the present invention so long as themodification does not prevent the dsRNA agent from possessingtransthyretin inhibitory activity. In one embodiment, one or moremodifications are made that enhance Dicer processing of the DsiRNA agent(an assay for determining Dicer processing of a DsiRNA is describedelsewhere herein). In a second embodiment, one or more modifications aremade that result in more effective transthyretin inhibition (asdescribed herein, transthyretin inhibition/transthyretin inhibitoryactivity of a dsRNA can be assayed via art-recognized methods fordetermining RNA levels, or for determining transthyretin polypeptidelevels, should such levels be assessed in lieu of or in addition toassessment of, e.g., transthyretin mRNA levels). In a third embodiment,one or more modifications are made that support greater transthyretininhibitory activity (means of determining transthyretin inhibitoryactivity are described supra). In a fourth embodiment, one or moremodifications are made that result in greater potency of transthyretininhibitory activity per each dsRNA agent molecule to be delivered to thecell (potency of transthyretin inhibitory activity is described supra).Modifications can be incorporated in the 3′-terminal region, the5′-terminal region, in both the 3′-terminal and 5′-terminal region or insome instances in various positions within the sequence. With therestrictions noted above in mind, numbers and combinations ofmodifications can be incorporated into the dsRNA agent. Where multiplemodifications are present, they may be the same or different.Modifications to bases, sugar moieties, the phosphate backbone, andtheir combinations are contemplated. Either 5′-terminus can bephosphorylated.

Examples of modifications contemplated for the phosphate backboneinclude phosphonates, including methylphosphonate, phosphorothioate, andphosphotriester modifications such as alkylphosphotriesters, and thelike. Examples of modifications contemplated for the sugar moietyinclude 2′-alkyl pyrimidine, such as 2′-O-methyl, 2′-fluoro, amino, anddeoxy modifications and the like (see, e.g., Amarzguioui et al., 2003,Nucleic Acids Research 31: 589-595). Examples of modificationscontemplated for the base groups include abasic sugars, 2-O-alkylmodified pyrimidines, 4-thiouracil, 5-bromouracil, 5-iodouracil, and5-(3-aminoallyl)-uracil and the like. Locked nucleic acids, or LNA's,could also be incorporated. Many other modifications are known and canbe used so long as the above criteria are satisfied. Examples ofmodifications are also disclosed in U.S. Pat. Nos. 5,684,143, 5,858,988and 6,291,438 and in U.S. published patent application No. 2004/0203145A1. Other modifications are disclosed in Herdewijn (2000, AntisenseNucleic Acid Drug Dev 10: 297-310), Eckstein (2000, Antisense NucleicAcid Drug Dev 10: 117-21), Rusckowski et al. (2000, Antisense NucleicAcid Drug Dev 10: 333-345), Stein et al. (2001, Antisense Nucleic AcidDrug Dev 11: 317-25); Vorobjev et al. (2001, Antisense Nucleic Acid DrugDev 11: 77-85).

One or more modifications contemplated can be incorporated into eitherstrand. The placement of the modifications in the dsRNA agent cangreatly affect the characteristics of the dsRNA agent, includingconferring greater potency and stability, reducing toxicity, enhanceDicer processing, and minimizing an immune response. In one embodiment,the antisense strand or the sense strand or both strands have one ormore 2′-O-methyl modified nucleotides. In another embodiment, theantisense strand contains 2′-O-methyl modified nucleotides. In anotherembodiment, the antisense stand contains a 3′ overhang that is comprisedof 2′-O-methyl modified nucleotides. The antisense strand could alsoinclude additional 2′-O-methyl modified nucleotides.

In certain embodiments, the anti-transthyretin DsiRNA agent of theinvention has several properties which enhance its processing by Dicer.According to such embodiments, the DsiRNA agent has a length sufficientsuch that it is processed by Dicer to produce an siRNA and at least oneof the following properties: (i) the DsiRNA agent is asymmetric, e.g.,has a 3′ overhang on the sense strand and (ii) the DsiRNA agent has amodified 3′ end on the antisense strand to direct orientation of Dicerbinding and processing of the dsRNA to an active siRNA. According tothese embodiments, the longest strand in the DsiRNA agent comprises25-30 nucleotides. In one embodiment, the sense strand comprises 25-30nucleotides and the antisense strand comprises 25-28 nucleotides. Thus,the resulting dsRNA has an overhang on the 3′ end of the sense strand.The overhang is 1-4 nucleotides, such as 2 nucleotides. The antisensestrand may also have a 5′ phosphate.

In certain embodiments, the sense strand of a DsiRNA agent is modifiedfor Dicer processing by suitable modifiers located at the 3′ end of thesense strand, i.e., the DsiRNA agent is designed to direct orientationof Dicer binding and processing. Suitable modifiers include nucleotidessuch as deoxyribonucleotides, dideoxyribonucleotides, acyclonucleotidesand the like and sterically hindered molecules, such as fluorescentmolecules and the like. Acyclonucleotides substitute a2-hydroxyethoxymethyl group for the 2′-deoxyribofuranosyl sugar normallypresent in dNMPs. Other nucleotide modifiers could include3′-deoxyadenosine (cordycepin), 3′-azido-3′-deoxythymidine (AZT),2′,3′-dideoxyinosine (ddI), 2′,3′-dideoxy-3′-thiacytidine (3TC),2′,3′-didehydro-2′,3′-dideoxythymidine (d4T) and the monophosphatenucleotides of 3′-azido-3′-deoxythymidine (AZT),2′,3′-dideoxy-3′-thiacytidine (3TC) and2′,3′-didehydro-2′,3′-dideoxythymidine (d4T). In one embodiment,deoxynucleotides are used as the modifiers. When nucleotide modifiersare utilized, 1-3 nucleotide modifiers, or 2 nucleotide modifiers aresubstituted for the ribonucleotides on the 3′ end of the sense strand.When sterically hindered molecules are utilized, they are attached tothe ribonucleotide at the 3′ end of the antisense strand. Thus, thelength of the strand does not change with the incorporation of themodifiers. In another embodiment, the invention contemplatessubstituting two DNA bases in the dsRNA to direct the orientation ofDicer processing. In a further invention, two terminal DNA bases arelocated on the 3′ end of the sense strand in place of tworibonucleotides forming a blunt end of the duplex on the 5′ end of theantisense strand and the 3′ end of the sense strand, and atwo-nucleotide RNA overhang is located on the 3′-end of the antisensestrand. This is an asymmetric composition with DNA on the blunt end andRNA bases on the overhanging end.

In certain other embodiments, the antisense strand of a DsiRNA agent ismodified for Dicer processing by suitable modifiers located at the 3′end of the antisense strand, i.e., the DsiRNA agent is designed todirect orientation of Dicer binding and processing. Suitable modifiersinclude nucleotides such as deoxyribonucleotides,dideoxyribonucleotides, acyclonucleotides and the like and stericallyhindered molecules, such as fluorescent molecules and the like.Acyclonucleotides substitute a 2-hydroxyethoxymethyl group for the2′-deoxyribofuranosyl sugar normally present in dNMPs. Other nucleotidemodifiers could include 3′-deoxyadenosine (cordycepin),3′-azido-3′-deoxythymidine (AZT), 2′,3′-dideoxyinosine (ddI),2′,3′-dideoxy-3′-thiacytidine (3TC),2′,3′-didehydro-2′,3′-dideoxythymidine (d4T) and the monophosphatenucleotides of 3′-azido-3′-deoxythymidine (AZT),2′,3′-dideoxy-3′-thiacytidine (3TC) and2′,3′-didehydro-2′,3′-dideoxythymidine (d4T). In one embodiment,deoxynucleotides are used as the modifiers. When nucleotide modifiersare utilized, 1-3 nucleotide modifiers, or 2 nucleotide modifiers aresubstituted for the ribonucleotides on the 3′ end of the antisensestrand. When sterically hindered molecules are utilized, they areattached to the ribonucleotide at the 3′ end of the antisense strand.Thus, the length of the strand does not change with the incorporation ofthe modifiers. In another embodiment, the invention contemplatessubstituting two DNA bases in the dsRNA to direct the orientation ofDicer processing. In a further invention, two terminal DNA bases arelocated on the 3′ end of the antisense strand in place of tworibonucleotides forming a blunt end of the duplex on the 5′ end of thesense strand and the 3′ end of the antisense strand, and atwo-nucleotide RNA overhang is located on the 3′-end of the sensestrand. This is also an asymmetric composition with DNA on the blunt endand RNA bases on the overhanging end.

The sense and antisense strands anneal under biological conditions, suchas the conditions found in the cytoplasm of a cell. In addition, aregion of one of the sequences, particularly of the antisense strand, ofthe dsRNA has a sequence length of at least 19 nucleotides, whereinthese nucleotides are adjacent to the 3′ end of antisense strand and aresufficiently complementary to a nucleotide sequence of the targettransthyretin RNA.

Additionally, the DsiRNA agent structure can be optimized to ensure thatthe oligonucleotide segment generated from Dicer's cleavage will be theportion of the oligonucleotide that is most effective in inhibiting geneexpression. For example, in one embodiment of the invention, a 27-bpoligonucleotide of the DsiRNA agent structure is synthesized wherein theanticipated 21 to 22-bp segment that will inhibit gene expression islocated on the 3′-end of the antisense strand. The remaining baseslocated on the 5′-end of the antisense strand will be cleaved by Dicerand will be discarded. This cleaved portion can be homologous (i.e.,based on the sequence of the target sequence) or non-homologous andadded to extend the nucleic acid strand.

US 2007/0265220 discloses that 27 mer DsiRNAs showed improved stabilityin serum over comparable 21 mer siRNA compositions, even absent chemicalmodification. Modifications of DsiRNA agents, such as inclusion of2′-O-methyl RNA in the antisense strand, in patterns such as detailedabove, when coupled with addition of a 5′ Phosphate, can improvestability of DsiRNA agents. Addition of 5′-phosphate to all strands insynthetic RNA duplexes may be an inexpensive and physiological method toconfer some limited degree of nuclease stability.

The chemical modification patterns of the dsRNA agents of the instantinvention are designed to enhance the efficacy of such agents.Accordingly, such modifications are designed to avoid reducing potencyof dsRNA agents; to avoid interfering with Dicer processing of DsiRNAagents; to improve stability in biological fluids (reduce nucleasesensitivity) of dsRNA agents; or to block or evade detection by theinnate immune system. Such modifications are also designed to avoidbeing toxic and to avoid increasing the cost or impact the ease ofmanufacturing the instant dsRNA agents of the invention.

In certain embodiments of the present invention, an anti-transthyretinDsiRNA agent has one or more of the following properties: (i) the DsiRNAagent is asymmetric, e.g., has a 3′ overhang on the antisense strand and(ii) the DsiRNA agent has a modified 3′ end on the sense strand todirect orientation of Dicer binding and processing of the dsRNA to anactive siRNA. According to this embodiment, the longest strand in thedsRNA comprises 25-35 nucleotides (e.g., 25, 26, 27, 28, 29, 30, 31, 32,33, 34 or 35 nucleotides). In certain such embodiments, the DsiRNA agentis asymmetric such that the sense strand comprises 25-34 nucleotides andthe 3′ end of the sense strand forms a blunt end with the 5′ end of theantisense strand while the antisense strand comprises 26-35 nucleotidesand forms an overhang on the 3′ end of the antisense strand. In oneembodiment, the DsiRNA agent is asymmetric such that the sense strandcomprises 25-28 nucleotides and the antisense strand comprises 25-30nucleotides. Thus, the resulting dsRNA has an overhang on the 3′ end ofthe antisense strand. The overhang is 1-4 nucleotides, for example 2nucleotides. The sense strand may also have a 5′ phosphate.

The DsiRNA agent can also have one or more of the following additionalproperties: (a) the antisense strand has a right shift from the typical21 mer (e.g., the DsiRNA comprises a length of antisense strandnucleotides that extends to the 5′ of a projected Dicer cleavage sitewithin the DsiRNA, with such antisense strand nucleotides base pairedwith corresponding nucleotides of the sense strand extending 3′ of aprojected Dicer cleavage site in the sense strand), (b) the strands maynot be completely complementary, i.e., the strands may contain simplemismatched base pairs (in certain embodiments, the DsiRNAs of theinvention possess 1, 2, 3, 4 or even 5 or more mismatched base pairs,provided that transthyretin inhibitory activity of the DsiRNA possessingmismatched base pairs is retained at sufficient levels (e.g., retains atleast 50% transthyretin inhibitory activity or more, at least 60%transthyretin inhibitory activity or more, at least 70% transthyretininhibitory activity or more, at least 80% transthyretin inhibitoryactivity or more, at least 90% transthyretin inhibitory activity or moreor at least 95% transthyretin inhibitory activity or more as compared toa corresponding DsiRNA not possessing mismatched base pairs. In certainembodiments, mismatched base pairs exist between the antisense and sensestrands of a DsiRNA. In some embodiments, mismatched base pairs exist(or are predicted to exist) between the antisense strand and the targetRNA. In certain embodiments, the presence of a mismatched base pair(s)between an antisense strand residue and a corresponding residue withinthe target RNA that is located 3′ in the target RNA sequence of aprojected Ago2 cleavage site retains and may even enhance transthyretininhibitory activity of a DsiRNA of the invention) and (c) basemodifications such as locked nucleic acid(s) may be included in the 5′end of the sense strand. A “typical” 21 mer siRNA is designed usingconventional techniques. In one technique, a variety of sites arecommonly tested in parallel or pools containing several distinct siRNAduplexes specific to the same target with the hope that one of thereagents will be effective (Ji et al., 2003, FEBS Lett 552: 247-252).Other techniques use design rules and algorithms to increase thelikelihood of obtaining active RNAi effector molecules (Schwarz et al.,2003, Cell 115: 199-208; Khvorova et al., 2003, Cell 115: 209-216;Ui-Tei et al., 2004, Nucleic Acids Res 32: 936-948; Reynolds et al.,2004, Nat Biotechnol 22: 326-330; Krol et al., 2004, J Biol Chem 279:42230-42239; Yuan et al., 2004, Nucl Acids Res 32 (Webserverissue):W130-134; Boese et al., 2005, Methods Enzymol 392: 73-96). Highthroughput selection of siRNA has also been developed (U.S. publishedpatent application No. 2005/0042641 A1). Potential target sites can alsobe analyzed by secondary structure predictions (Heale et al., 2005,Nucleic Acids Res 33(3): e30). This 21 mer is then used to design aright shift to include 3-9 additional nucleotides on the 5′ end of the21 mer. The sequence of these additional nucleotides is not restricted.In one embodiment, the added ribonucleotides are based on the sequenceof the target gene. Even in this embodiment, full complementaritybetween the target sequence and the antisense siRNA is not required.

The first and second oligonucleotides of a DsiRNA agent of the instantinvention are not required to be completely complementary. They onlyneed to be sufficiently complementary to anneal under biologicalconditions and to provide a substrate for Dicer that produces a siRNAsufficiently complementary to the target sequence. Locked nucleic acids,or LNA's, are well known to a skilled artisan (Elmen et al., 2005,Nucleic Acids Res 33: 439-447; Kurreck et al., 2002, Nucleic Acids Res30: 1911-1918; Crinelli et al., 2002, Nucleic Acids Res 30: 2435-2443;Braasch and Corey, 2001, Chem Biol 8: 1-7; Bondensgaard et al., 2000,Chemistry 6: 2687-2695; Wahlestedt et al., 2000, Proc Natl Acad Sci USA97: 5633-5638). In one embodiment, an LNA is incorporated at the 5′terminus of the sense strand. In another embodiment, an LNA isincorporated at the 5′ terminus of the sense strand in duplexes designedto include a 3′ overhang on the antisense strand.

In certain embodiments, the DsiRNA agent of the instant invention has anasymmetric structure, with the sense strand having a 25-base pairlength, and the antisense strand having a 27-base pair length with a 2base 3′-overhang. In other embodiments, this DsiRNA agent having anasymmetric structure further contains 2 deoxynucleotides at the 3′ endof the sense strand in place of two of the ribonucleotides.

Certain DsiRNA agent compositions containing two separateoligonucleotides can be linked by a third structure. The third structurewill not block Dicer activity on the DsiRNA agent and will not interferewith the directed destruction of the RNA transcribed from the targetgene. In one embodiment, the third structure may be a chemical linkinggroup. Many suitable chemical linking groups are known in the art andcan be used. Alternatively, the third structure may be anoligonucleotide that links the two oligonucleotides of the DsiRNA agentin a manner such that a hairpin structure is produced upon annealing ofthe two oligonucleotides making up the dsRNA composition. The hairpinstructure will not block Dicer activity on the DsiRNA agent and will notinterfere with the directed destruction of the transthyretin RNA.

Transthyretin cDNA and Polypeptide Sequences

Known human and mouse transthyretin cDNA and polypeptide sequencesinclude the following: human transthyretin NM_000371.3 and correspondinghuman transthyretin polypeptide sequence GenBank Accession No.NP_000362.1; and mouse wild-type transthyretin sequence GenBankAccession No. NM_013697.5 (Mus musculus C57BL/6 Transthyretin) andcorresponding mouse transthyretin sequence GenBank Accession No.NP_038725.1.

In Vitro Assay to Assess dsRNA Transthyretin Inhibitory Activity

An in vitro assay that recapitulates RNAi in a cell-free system can beused to evaluate dsRNA constructs targeting transthyretin RNAsequence(s), and thus to assess transthyretin-specific gene inhibitoryactivity (also referred to herein as transthyretin inhibitory activity)of a dsRNA. The assay comprises the system described by Tuschl et al.,1999, Genes and Development, 13, 3191-3197 and Zamore et al., 2000,Cell, 101, 25-33 adapted for use with dsRNA (e.g., DsiRNA) agentsdirected against transthyretin RNA. A Drosophila extract derived fromsyncytial blastoderm is used to reconstitute RNAi activity in vitro.Target RNA is generated via in vitro transcription from a selectedtransthyretin expressing plasmid using T7 RNA polymerase or via chemicalsynthesis. Sense and antisense dsRNA strands (for example, 20 uM each)are annealed by incubation in buffer (such as 100 mM potassium acetate,30 mM HEPES-KOH, pH 7.4, 2 mM magnesium acetate) for 1 minute at 90° C.followed by 1 hour at 37° C., then diluted in lysis buffer (for example100 mM potassium acetate, 30 mM HEPES-KOH at pH 7.4, 2 mM magnesiumacetate). Annealing can be monitored by gel electrophoresis on anagarose gel in TBE buffer and stained with ethidium bromide. TheDrosophila lysate is prepared using zero to two-hour-old embryos fromOregon R flies collected on yeasted molasses agar that are dechorionatedand lysed. The lysate is centrifuged and the supernatant isolated. Theassay comprises a reaction mixture containing 50% lysate [vol/vol], RNA(10-50 pM final concentration), and 10% [vol/vol] lysis buffercontaining dsRNA (10 nM final concentration). The reaction mixture alsocontains 10 mM creatine phosphate, 10 ug/ml creatine phosphokinase, 100um GTP, 100 uM UTP, 100 uM CTP, 500 uM ATP, 5 mM DTT, 0.1 U/uL RNasin(Promega), and 100 uM of each amino acid. The final concentration ofpotassium acetate is adjusted to 100 mM. The reactions are pre-assembledon ice and preincubated at 25° C. for 10 minutes before adding RNA, thenincubated at 25° C. for an additional 60 minutes. Reactions are quenchedwith 4 volumes of 1.25×Passive Lysis Buffer (Promega). Target RNAcleavage is assayed by RT-PCR analysis or other methods known in the artand are compared to control reactions in which dsRNA is omitted from thereaction.

Alternately, internally-labeled target RNA for the assay is prepared byin vitro transcription in the presence of [α-³²P] CTP, passed over a G50Sephadex column by spin chromatography and used as target RNA withoutfurther purification. Optionally, target RNA is 5′-³²P-end labeled usingT4 polynucleotide kinase enzyme. Assays are performed as described aboveand target RNA and the specific RNA cleavage products generated by RNAiare visualized on an autoradiograph of a gel. The percentage of cleavageis determined by PHOSPHOR IMAGER® (autoradiography) quantitation ofbands representing intact control RNA or RNA from control reactionswithout dsRNA and the cleavage products generated by the assay.

In one embodiment, this assay is used to determine target sites in thetransthyretin RNA target for dsRNA mediated RNAi cleavage, wherein aplurality of dsRNA constructs are screened for RNAi mediated cleavage ofthe transthyretin RNA target, for example, by analyzing the assayreaction by electrophoresis of labeled target RNA, or by northernblotting, as well as by other methodology well known in the art.

In certain embodiments, a dsRNA of the invention is deemed to possesstransthyretin inhibitory activity if, e.g., a 50% reduction intransthyretin RNA levels is observed in a system, cell, tissue ororganism, relative to a suitable control. Additional metes and boundsfor determination of transthyretin inhibitory activity of a dsRNA of theinvention are described supra.

Conjugation and Delivery of Anti-Transthyretin dsRNA Agents

In certain embodiments, the present invention relates to a method fortreating a subject having a transthyretin-associated disease ordisorder, or at risk of developing a transthyretin-associated disease ordisorder. In such embodiments, the dsRNA can act as novel therapeuticagents for controlling the transthyretin-associated disease or disorder.The method comprises administering a pharmaceutical composition of theinvention to the patient (e.g., human), such that the expression, leveland/or activity of a transthyretin RNA is reduced. The expression, leveland/or activity of a polypeptide encoded by a transthyretin RNA mightalso be reduced by a dsRNA of the instant invention, even where saiddsRNA is directed against a non-coding region of the transthyretintranscript (e.g., a targeted 5′ UTR or 3′ UTR sequence). Because oftheir high specificity, the dsRNAs of the present invention canspecifically target transthyretin sequences of cells and tissues,optionally in an allele-specific manner where polymorphic alleles existwithin an individual and/or population.

In the treatment of a transthyretin-associated disease or disorder, thedsRNA can be brought into contact with the cells or tissue of a subject,e.g., the cells or tissue of a subject exhibiting disregulation oftransthyretin and/or otherwise targeted for reduction of transthyretinlevels. For example, dsRNA substantially identical to all or part of atransthyretin RNA sequence, may be brought into contact with orintroduced into such a cell, either in vivo or in vitro. Similarly,dsRNA substantially identical to all or part of a transthyretin RNAsequence may administered directly to a subject having or at risk ofdeveloping a transthyretin-associated disease or disorder.

Therapeutic use of the dsRNA agents of the instant invention can involveuse of formulations of dsRNA agents comprising multiple different dsRNAagent sequences. For example, two or more, three or more, four or more,five or more, etc. of the presently described agents can be combined toproduce a formulation that, e.g., targets multiple different regions ofthe transthyretin RNA, or that not only target transthyretin RNA butalso target, e.g., cellular target genes associated with atransthyretin-associated disease or disorder. A dsRNA agent of theinstant invention may also be constructed such that either strand of thedsRNA agent independently targets two or more regions of transthyretinRNA, or such that one of the strands of the dsRNA agent targets acellular target gene of transthyretin known in the art.

Use of multifunctional dsRNA molecules that target more then one regionof a target nucleic acid molecule can also provide potent inhibition oftransthyretin RNA levels and expression. For example, a singlemultifunctional dsRNA construct of the invention can target both thetransthyretin-242 and transthyretin-439 sites simultaneously;additionally and/or alternatively, single or multifunctional agents ofthe invention can be designed to selectively target one splice variantof transthyretin over another.

Thus, the dsRNA agents of the instant invention, individually, or incombination or in conjunction with other drugs, can be used to treat,inhibit, reduce, or prevent a transthyretin-associated disease ordisorder. For example, the dsRNA molecules can be administered to asubject or can be administered to other appropriate cells evident tothose skilled in the art, individually or in combination with one ormore drugs under conditions suitable for the treatment.

The dsRNA molecules also can be used in combination with other knowntreatments to treat, inhibit, reduce, or prevent atransthyretin-associated disease or disorder in a subject or organism.For example, the described molecules could be used in combination withone or more known compounds, treatments, or procedures to treat,inhibit, reduce, or prevent a transthyretin-associated disease ordisorder in a subject or organism as are known in the art.

A dsRNA agent of the invention can be conjugated (e.g., at its 5′ or 3′terminus of its sense or antisense strand) or unconjugated to anothermoiety (e.g. a non-nucleic acid moiety such as a peptide), an organiccompound (e.g., a dye, cholesterol, or the like). Modifying dsRNA agentsin this way may improve cellular uptake or enhance cellular targetingactivities of the resulting dsRNA agent derivative as compared to thecorresponding unconjugated dsRNA agent, are useful for tracing the dsRNAagent derivative in the cell, or improve the stability of the dsRNAagent derivative compared to the corresponding unconjugated dsRNA agent.

In certain embodiments, specific exemplary forms of dsRNA conjugates arecontemplated. Notably, RNAi therapies, such as the dsRNAs that arespecifically exemplified herein, have demonstrated particularly goodability to be delivered to the cells of the liver in vivo (via, e.g.,lipid nanoparticles and/or conjugates such as dynamic polyconjugates orGalNAc conjugates—in certain exemplary embodiments, one or more GalNAcmoieties can be conjugated to a 3′- and/or 5′-overhang region of a dsNA,optionally to an “extended” overhang region of a dsNA (e.g., to a 5 ormore nucleotide, 8 or more nucleotide, etc. example of such anoverhang); additionally and/or alternatively, one or more GaNAc moietiescan be conjugated to ds extended regions of a dsNA, e.g., to the duplexregion formed by the 5′-end region of the guide/antisense strand of adsNA and the corresponding 3′-end region of the passenger/sense strandof a dsNA and/or to the duplex region formed by the 3′-end region of theguide/antisense strand of a dsNA and the corresponding 5′-end region ofthe passenger/sense strand of a dsNA). Thus, formulated RNAi therapies,such as those described herein, are attractive modalities for treatingor preventing diseases or disorders that are present in, originate in orotherwise involve the liver.

Methods of Introducing Nucleic Acids, Vectors, and Host Cells

dsRNA agents of the invention may be directly introduced into a cell(i.e., intracellularly); or introduced extracellularly into a cavity,interstitial space, into the circulation of an organism, introducedorally, or may be introduced by bathing a cell or organism in a solutioncontaining the nucleic acid. Vascular or extravascular circulation, theblood or lymph system, and the cerebrospinal fluid are sites where thenucleic acid may be introduced.

The dsRNA agents of the invention can be introduced using nucleic aciddelivery methods known in art including injection of a solutioncontaining the nucleic acid, bombardment by particles covered by thenucleic acid, soaking the cell or organism in a solution of the nucleicacid, or electroporation of cell membranes in the presence of thenucleic acid. Other methods known in the art for introducing nucleicacids to cells may be used, such as lipid-mediated carrier transport,chemical-mediated transport, and cationic liposome transfection such ascalcium phosphate, and the like. The nucleic acid may be introducedalong with other components that perform one or more of the followingactivities: enhance nucleic acid uptake by the cell or otherwiseincrease inhibition of the target transthyretin RNA.

A cell having a target transthyretin RNA may be from the germ line orsomatic, totipotent or pluripotent, dividing or non-dividing, parenchymaor epithelium, immortalized or transformed, or the like. The cell may bea stem cell or a differentiated cell. Cell types that are differentiatedinclude adipocytes, fibroblasts, myocytes, cardiomyocytes, endothelium,neurons, glia, blood cells, megakaryocytes, lymphocytes, macrophages,neutrophils, eosinophils, basophils, mast cells, leukocytes,granulocytes, keratinocytes, chondrocytes, osteoblasts, osteoclasts,hepatocytes, and cells of the endocrine or exocrine glands.

Depending on the particular target transthyretin RNA sequence and thedose of dsRNA agent material delivered, this process may provide partialor complete loss of function for the transthyretin RNA. A reduction orloss of RNA levels or expression (either transthyretin RNA expression orencoded polypeptide expression) in at least 50%, 60%, 70%, 80%, 90%, 95%or 99% or more of targeted cells is exemplary. Inhibition oftransthyretin RNA levels or expression refers to the absence (orobservable decrease) in the level of transthyretin RNA or transthyretinRNA-encoded protein. Specificity refers to the ability to inhibit thetransthyretin RNA without manifest effects on other genes of the cell.The consequences of inhibition can be confirmed by examination of theoutward properties of the cell or organism or by biochemical techniquessuch as RNA solution hybridization, nuclease protection, Northernhybridization, reverse transcription, gene expression monitoring with amicroarray, antibody binding, enzyme linked immunosorbent assay (ELISA),Western blotting, radioimmunoassay (RIA), other immunoassays, andfluorescence activated cell analysis (FACS). Inhibition of targettransthyretin RNA sequence(s) by the dsRNA agents of the invention alsocan be measured based upon the effect of administration of such dsRNAagents upon development/progression of a transthyretin-associateddisease or disorder, e.g., tumor formation, growth, metastasis, etc.,either in vivo or in vitro. Treatment and/or reductions in tumor orcancer cell levels can include halting or reduction of growth of tumoror cancer cell levels or reductions of, e.g., 10%, 20%, 30%, 40%, 50%,60%, 70%, 80%, 90%, 95% or 99% or more, and can also be measured inlogarithmic terms, e.g., 10-fold, 100-fold, 1000-fold, 10⁵-fold,10⁶-fold, 10⁷-fold reduction in cancer cell levels could be achieved viaadministration of the dsRNA agents of the invention to cells, a tissue,or a subject.

For RNA-mediated inhibition in a cell line or whole organism, expressiona reporter or drug resistance gene whose protein product is easilyassayed can be measured. Such reporter genes include acetohydroxyacidsynthase (AHAS), alkaline phosphatase (AP), beta galactosidase (LacZ),beta glucoronidase (GUS), chloramphenicol acetyltransferase (CAT), greenfluorescent protein (GFP), horseradish peroxidase (HRP), luciferase(Luc), nopaline synthase (NOS), octopine synthase (OCS), and derivativesthereof. Multiple selectable markers are available that conferresistance to ampicillin, bleomycin, chloramphenicol, gentamycin,hygromycin, kanamycin, lincomycin, methotrexate, phosphinothricin,puromycin, and tetracyclin. Depending on the assay, quantitation of theamount of gene expression allows one to determine a degree of inhibitionwhich is greater than 10%, 33%, 50%, 90%, 95% or 99% as compared to acell not treated according to the present invention.

Lower doses of injected material and longer times after administrationof RNA silencing agent may result in inhibition in a smaller fraction ofcells (e.g., at least 10%, 20%, 50%, 75%, 90%, or 95% of targetedcells). Quantitation of gene expression in a cell may show similaramounts of inhibition at the level of accumulation of targettransthyretin RNA or translation of target protein. As an example, theefficiency of inhibition may be determined by assessing the amount ofgene product in the cell; RNA may be detected with a hybridization probehaving a nucleotide sequence outside the region used for the inhibitorydsRNA, or translated polypeptide may be detected with an antibody raisedagainst the polypeptide sequence of that region.

The dsRNA agent may be introduced in an amount which allows delivery ofat least one copy per cell. Higher doses (e.g., at least 5, 10, 100, 500or 1000 copies per cell) of material may yield more effectiveinhibition; lower doses may also be useful for specific applications.

Transthyretin Biology

Transthyretin (TTR) is a secreted thyroid hormone-binding protein. TTRbinds and transports retinol binding protein (RBP)/Vitamin A, and serumthyroxine (T4) in plasma and cerebrospinal fluid.

In cerebrospinal fluid, TTR is the primary carrier of T4. TTR also actsas a carrier of retinol (vitamin A) through its association withretinol-binding protein (RBP) in the blood and the CSF. Less than 1% ofTTR's T4 binding sites are occupied in blood, which helps to preventTTR's dissociation, misfolding and aggregation, which can provokedegeneration of post-mitotic tissue.

Numerous other small molecules are known to bind in the thyroxinebinding sites, including many natural products (such as resveratrol),drugs (Tafamidis (Razavi et al. Angew. Chem. Int. Ed. Engl. 42 (24):2758-61), or Vyndaqel, diflunisal (Sekijima et al. Amyloid 13 (4):236-49; Adamski-Wemer et al. J. Med. Chem. 47 (2): 355-74; Vilaro et al.XIth International Symposium on Amyloidosis. Boca Raton: CRC),flufenamic acid (Baures et al. Bioorg. Med. Chem. 7 (7): 1339-47)), andtoxins (PCB (Purkey et al. Chem. Biol. 11 (12): 1719-28)).

TTR is a 55 kDa homotetramer with a dimer of dimers quaternary structurethat is synthesized in the liver, choroid plexus and retinal pigmentepithelium for secretion into the bloodstream, cerebrospinal fluid andthe eye, respectively. Each monomer is a 127-residue polypeptide rich inbeta sheet structure. Association of two monomers via their edgebeta-strands forms an extended beta sandwich. Further association of twoof these dimers in a face-to-face fashion produces the homotetramericstructure and creates the two thyroxine binding sites per tetramer. Thisdimer-dimer interface, comprising the two T4 binding sites, is theweaker dimer-dimer interface and is the one that comes apart first inthe process of tetramer dissociation (Foss et al. Biochemistry 44:15525-33).

Because TTR is primarily produced in the liver, replacement of a livercontaining a mutant TTR gene with a normal gene is able to reduce themutant TTR levels in the body to <5% of pretransplant levels. Certainmutations, however, cause CNS amyloidosis, and due to the theirproduction by the choroid plexus, the CNS TTR amyloid diseases do notrespond to gene therapy mediated by liver transplantation. In 2011, theEuropean Medicines Agency approved Tafamidis or Vyndagel (Razavi et al.Angew. Chem. Int. Ed. Engl. 42 (24): 2758-61) for the amelioration ofFAP. Vyndagel kinetically stabilizes the TTR tetramer, preventingtetramer dissociation required for TTR amyloidogenesis and degradationof the autonomic nervous system (Ando and Suhr. Amyloid 5: 288-300)and/or the peripheral nervous system and/or the heart (Hammarstrom etal. Science 299: 713-6).

TTR is also thought to have beneficial side, as it binds beta-amyloidprotein, thereby preventing beta-amyloid accumulation into plaquesassociated with the early stages of Alzheimer's Disease. Preventingplaque formation is believed to enable a cell to rid itself of thisotherwise toxic protein form and, thus, help prevent and maybe eventreat the disease (Li and Buxbaum. Molecular Neurodegeneration 6: 79).

There is now strong genetic (Coelho et al. J Rheumatol 20, 179;Hammarstrom et al. Science 293: 2459-62) and pharmacologic dataindicating that the process of amyloid fibril formation leads to thedegeneration of post-mitotic tissue causing FAP and likely FAC and SSA.Evidence points to the oligomers generated in the process ofamyloidogenicity leading to the observed proteotoxicity (Sousa et al.Am. J. Pathol. 159: 1993-2000; Reixach et al. Proc. Natl. Acad. Sci.U.S.A. 101: 2817-22).

Transthyretin level in cerebrospinal fluid has also been found to belower in patients with some neurobiological disorders such asschizophrenia (Huang et al. PLoS Med. 3: e428). The reduced level oftransthyretin in the CSF may indicate a lower thyroxine transport inbrains of patients with schizophrenia.

Because transthyretin is made in part by the choroid plexus, it can alsobe used as an immunohistochemical marker for choroid plexus papillomas.

In medicine, nutritional status can be assessed by measuring theconcentration of transthyretin in the blood. In theory, other transportproteins such as albumin or transferrin could be used, but transthyretinis preferred because of its shorter half-life, although this means thatits concentration more closely reflects recent dietary intake ratherthan overall nutritional status (Shenkin, Alan Clin Chem 52: 2177-2179).Transthyretin concentration has been shown to be a good indicator ofwhether or not a malnourished patient will develop refeeding syndromeupon commencement of refeeding, via either the enteral, parenteral ororal routes (Marik and Bedigian. Arch Surg 131 (10): 1043-1047).

Transthyretin has been shown to interact with Perlecan (Smeland et al.Biochem. J. (England) 326: 829-36).

Pharmaceutical Compositions

In certain embodiments, the present invention provides for apharmaceutical composition comprising the dsRNA agent of the presentinvention. The dsRNA agent sample can be suitably formulated andintroduced into the environment of the cell by any means that allows fora sufficient portion of the sample to enter the cell to induce genesilencing, if it is to occur. Many formulations for dsRNA are known inthe art and can be used so long as the dsRNA gains entry to the targetcells so that it can act. See, e.g., U.S. published patent applicationNos. 2004/0203145 A1 and 2005/0054598 A1. For example, the dsRNA agentof the instant invention can be formulated in buffer solutions such asphosphate buffered saline solutions, liposomes, micellar structures, andcapsids. Formulations of dsRNA agent with cationic lipids can be used tofacilitate transfection of the dsRNA agent into cells. For example,cationic lipids, such as lipofectin (U.S. Pat. No. 5,705,188), cationicglycerol derivatives, and polycationic molecules, such as polylysine(published PCT International Application WO 97/30731), can be used.Suitable lipids include Oligofectamine, Lipofectamine (LifeTechnologies), NC388 (Ribozyme Pharmaceuticals, Inc., Boulder, Colo.),or FuGene 6 (Roche) all of which can be used according to themanufacturer's instructions.

Such compositions typically include the nucleic acid molecule and apharmaceutically acceptable carrier. As used herein the language“pharmaceutically acceptable carrier” includes saline, solvents,dispersion media, coatings, antibacterial and antifungal agents,isotonic and absorption delaying agents, and the like, compatible withpharmaceutical administration. Supplementary active compounds can alsobe incorporated into the compositions.

A pharmaceutical composition is formulated to be compatible with itsintended route of administration. Examples of routes of administrationinclude parenteral, e.g., intravenous, intradermal, subcutaneous, oral(e.g., inhalation), transdermal (topical), transmucosal, and rectaladministration. Solutions or suspensions used for parenteral,intradermal, or subcutaneous application can include the followingcomponents: a sterile diluent such as water for injection, salinesolution, fixed oils, polyethylene glycols, glycerine, propylene glycolor other synthetic solvents; antibacterial agents such as benzyl alcoholor methyl parabens; antioxidants such as ascorbic acid or sodiumbisulfite; chelating agents such as ethylenediaminetetraacetic acid;buffers such as acetates, citrates or phosphates and agents for theadjustment of tonicity such as sodium chloride or dextrose. pH can beadjusted with acids or bases, such as hydrochloric acid or sodiumhydroxide. The parenteral preparation can be enclosed in ampoules,disposable syringes or multiple dose vials made of glass or plastic.

Pharmaceutical compositions suitable for injectable use include sterileaqueous solutions (where water soluble) or dispersions and sterilepowders for the extemporaneous preparation of sterile injectablesolutions or dispersion. For intravenous administration, suitablecarriers include physiological saline, bacteriostatic water, CremophorEL™ (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS). In allcases, the composition must be sterile and should be fluid to the extentthat easy syringability exists. It should be stable under the conditionsof manufacture and storage and must be preserved against thecontaminating action of microorganisms such as bacteria and fungi. Thecarrier can be a solvent or dispersion medium containing, for example,water, ethanol, polyol (for example, glycerol, propylene glycol, andliquid polyetheylene glycol, and the like), and suitable mixturesthereof. The proper fluidity can be maintained, for example, by the useof a coating such as lecithin, by the maintenance of the requiredparticle size in the case of dispersion and by the use of surfactants.Prevention of the action of microorganisms can be achieved by variousantibacterial and antifungal agents, for example, parabens,chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In manycases, it will be preferable to include isotonic agents, for example,sugars, polyalcohols such as manitol, sorbitol, sodium chloride in thecomposition. Prolonged absorption of the injectable compositions can bebrought about by including in the composition an agent which delaysabsorption, for example, aluminum monostearate and gelatin.

Sterile injectable solutions can be prepared by incorporating the activecompound in the required amount in a selected solvent with one or acombination of ingredients enumerated above, as required, followed byfiltered sterilization. Generally, dispersions are prepared byincorporating the active compound into a sterile vehicle, which containsa basic dispersion medium and the required other ingredients from thoseenumerated above. In the case of sterile powders for the preparation ofsterile injectable solutions, the preferred methods of preparation arevacuum drying and freeze-drying which yields a powder of the activeingredient plus any additional desired ingredient from a previouslysterile-filtered solution thereof.

Oral compositions generally include an inert diluent or an ediblecarrier. For the purpose of oral therapeutic administration, the activecompound can be incorporated with excipients and used in the form oftablets, troches, or capsules, e.g., gelatin capsules. Oral compositionscan also be prepared using a fluid carrier for use as a mouthwash.Pharmaceutically compatible binding agents, and/or adjuvant materialscan be included as part of the composition. The tablets, pills,capsules, troches and the like can contain any of the followingingredients, or compounds of a similar nature: a binder such asmicrocrystalline cellulose, gum tragacanth or gelatin; an excipient suchas starch or lactose, a disintegrating agent such as alginic acid,Primogel, or corn starch; a lubricant such as magnesium stearate orSterotes; a glidant such as colloidal silicon dioxide; a sweeteningagent such as sucrose or saccharin; or a flavoring agent such aspeppermint, methyl salicylate, or orange flavoring.

For administration by inhalation, the compounds are delivered in theform of an aerosol spray from pressured container or dispenser whichcontains a suitable propellant, e.g., a gas such as carbon dioxide, or anebulizer. Such methods include those described in U.S. Pat. No.6,468,798.

Systemic administration can also be by transmucosal or transdermalmeans. For transmucosal or transdermal administration, penetrantsappropriate to the barrier to be permeated are used in the formulation.Such penetrants are generally known in the art, and include, forexample, for transmucosal administration, detergents, bile salts, andfusidic acid derivatives. Transmucosal administration can beaccomplished through the use of nasal sprays or suppositories. Fortransdermal administration, the active compounds are formulated intoointments, salves, gels, or creams as generally known in the art.

The compounds can also be prepared in the form of suppositories (e.g.,with conventional suppository bases such as cocoa butter and otherglycerides) or retention enemas for rectal delivery.

The compounds can also be administered by transfection or infectionusing methods known in the art, including but not limited to the methodsdescribed in McCaffrey et al. (2002), Nature, 418(6893), 38-9(hydrodynamic transfection); Xia et al. (2002), Nature Biotechnol.,20(10), 1006-10 (viral-mediated delivery); or Putnam (1996), Am. J.Health Syst. Pharm. 53(2), 151-160, erratum at Am. J. Health Syst.Pharm. 53(3), 325 (1996).

The compounds can also be administered by a method suitable foradministration of nucleic acid agents, such as a DNA vaccine. Thesemethods include gene guns, bio injectors, and skin patches as well asneedle-free methods such as the micro-particle DNA vaccine technologydisclosed in U.S. Pat. No. 6,194,389, and the mammalian transdermalneedle-free vaccination with powder-form vaccine as disclosed in U.S.Pat. No. 6,168,587. Additionally, intranasal delivery is possible, asdescribed in, inter alia, Hamajima et al. (1998), Clin. Immunol.Immunopathol., 88(2), 205-10. Liposomes (e.g., as described in U.S. Pat.No. 6,472,375) and microencapsulation can also be used. Biodegradabletargetable microparticle delivery systems can also be used (e.g., asdescribed in U.S. Pat. No. 6,471,996).

In one embodiment, the active compounds are prepared with carriers thatwill protect the compound against rapid elimination from the body, suchas a controlled release formulation, including implants andmicroencapsulated delivery systems. Biodegradable, biocompatiblepolymers can be used, such as ethylene vinyl acetate, polyanhydrides,polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Suchformulations can be prepared using standard techniques. The materialscan also be obtained commercially from Alza Corporation and NovaPharmaceuticals, Inc. Liposomal suspensions (including liposomestargeted to infected cells with monoclonal antibodies to viral antigens)can also be used as pharmaceutically acceptable carriers. These can beprepared according to methods known to those skilled in the art, forexample, as described in U.S. Pat. No. 4,522,811.

Toxicity and therapeutic efficacy of such compounds can be determined bystandard pharmaceutical procedures in cell cultures or experimentalanimals, e.g., for determining the LD₅₀ (the dose lethal to 50% of thepopulation) and the ED₅₀ (the dose therapeutically effective in 50% ofthe population). The dose ratio between toxic and therapeutic effects isthe therapeutic index and it can be expressed as the ratio LD₅₀/ED₅₀.Compounds which exhibit high therapeutic indices are preferred. Whilecompounds that exhibit toxic side effects may be used, care should betaken to design a delivery system that targets such compounds to thesite of affected tissue in order to minimize potential damage touninfected cells and, thereby, reduce side effects.

The data obtained from the cell culture assays and animal studies can beused in formulating a range of dosage for use in humans. The dosage ofsuch compounds lies preferably within a range of circulatingconcentrations that include the ED₅₀ with little or no toxicity. Thedosage may vary within this range depending upon the dosage formemployed and the route of administration utilized. For a compound usedin the method of the invention, the therapeutically effective dose canbe estimated initially from cell culture assays. A dose may beformulated in animal models to achieve a circulating plasmaconcentration range that includes the IC₅₀ (i.e., the concentration ofthe test compound which achieves a half-maximal inhibition of symptoms)as determined in cell culture. Such information can be used to moreaccurately determine useful doses in humans. Levels in plasma may bemeasured, for example, by high performance liquid chromatography.

As defined herein, a therapeutically effective amount of a nucleic acidmolecule (i.e., an effective dosage) depends on the nucleic acidselected. For instance, single dose amounts of a dsRNA (or, e.g., aconstruct(s) encoding for such dsRNA) in the range of approximately 1 pgto 1000 mg may be administered; in some embodiments, 10, 30, 100, or1000 pg, or 10, 30, 100, or 1000 ng, or 10, 30, 100, or 1000 μg, or 10,30, 100, or 1000 mg may be administered. In some embodiments, 1-5 g ofthe compositions can be administered. The compositions can beadministered one from one or more times per day to one or more times perweek; including once every other day. The skilled artisan willappreciate that certain factors may influence the dosage and timingrequired to effectively treat a subject, including but not limited tothe severity of the disease or disorder, previous treatments, thegeneral health and/or age of the subject, and other diseases present.Moreover, treatment of a subject with a therapeutically effective amountof a nucleic acid (e.g., dsRNA), protein, polypeptide, or antibody caninclude a single treatment or, preferably, can include a series oftreatments. The nucleic acid molecules of the invention can be insertedinto expression constructs, e.g., viral vectors, retroviral vectors,expression cassettes, or plasmid viral vectors, e.g., using methodsknown in the art, including but not limited to those described in Xia etal., (2002), supra. Expression constructs can be delivered to a subjectby, for example, inhalation, orally, intravenous injection, localadministration (see U.S. Pat. No. 5,328,470) or by stereotacticinjection (see e.g., Chen et al. (1994), Proc. Natl. Acad. Sci. USA, 91,3054-3057). The pharmaceutical preparation of the delivery vector caninclude the vector in an acceptable diluent, or can comprise a slowrelease matrix in which the delivery vehicle is imbedded. Alternatively,where the complete delivery vector can be produced intact fromrecombinant cells, e.g., retroviral vectors, the pharmaceuticalpreparation can include one or more cells which produce the genedelivery system.

The expression constructs may be constructs suitable for use in theappropriate expression system and include, but are not limited toretroviral vectors, linear expression cassettes, plasmids and viral orvirally-derived vectors, as known in the art. Such expression constructsmay include one or more inducible promoters, RNA Pol III promotersystems such as U6 snRNA promoters or H1 RNA polymerase III promoters,or other promoters known in the art. The constructs can include one orboth strands of the siRNA. Expression constructs expressing both strandscan also include loop structures linking both strands, or each strandcan be separately transcribed from separate promoters within the sameconstruct. Each strand can also be transcribed from a separateexpression construct, e.g., Tuschl (2002, Nature Biotechnol 20:500-505).

It can be appreciated that the method of introducing dsRNA agents intothe environment of the cell will depend on the type of cell and the makeup of its environment. For example, when the cells are found within aliquid, one preferable formulation is with a lipid formulation such asin lipofectamine and the dsRNA agents can be added directly to theliquid environment of the cells. Lipid formulations can also beadministered to animals such as by intravenous, intramuscular, orintraperitoneal injection, or orally or by inhalation or other methodsas are known in the art. When the formulation is suitable foradministration into animals such as mammals and more specificallyhumans, the formulation is also pharmaceutically acceptable.Pharmaceutically acceptable formulations for administeringoligonucleotides are known and can be used. In some instances, it may bepreferable to formulate dsRNA agents in a buffer or saline solution anddirectly inject the formulated dsRNA agents into cells, as in studieswith oocytes. The direct injection of dsRNA agent duplexes may also bedone. For suitable methods of introducing dsRNA (e.g., DsiRNA agents),see U.S. published patent application No. 2004/0203145 A1.

Suitable amounts of a dsRNA agent must be introduced and these amountscan be empirically determined using standard methods. Typically,effective concentrations of individual dsRNA agent species in theenvironment of a cell will be 50 nanomolar or less, 10 nanomolar orless, or compositions in which concentrations of 1 nanomolar or less canbe used. In another embodiment, methods utilizing a concentration of 200picomolar or less, 100 picomolar or less, 50 picomolar or less, 20picomolar or less, and even a concentration of 10 picomolar or less, 5picomolar or less, 2 picomolar or less or 1 picomolar or less can beused in many circumstances.

The method can be carried out by addition of the dsRNA agentcompositions to an extracellular matrix in which cells can live providedthat the dsRNA agent composition is formulated so that a sufficientamount of the dsRNA agent can enter the cell to exert its effect. Forexample, the method is amenable for use with cells present in a liquidsuch as a liquid culture or cell growth media, in tissue explants, or inwhole organisms, including animals, such as mammals and especiallyhumans.

The level or activity of a transthyretin RNA can be determined by asuitable method now known in the art or that is later developed. It canbe appreciated that the method used to measure a target RNA and/or theexpression of a target RNA can depend upon the nature of the target RNA.For example, where the target transthyretin RNA sequence encodes aprotein, the term “expression” can refer to a protein or thetransthyretin RNA/transcript derived from the transthyretin gene (eithergenomic or of exogenous origin). In such instances the expression of thetarget transthyretin RNA can be determined by measuring the amount oftransthyretin RNA/transcript directly or by measuring the amount oftransthyretin protein. Protein can be measured in protein assays such asby staining or immunoblotting or, if the protein catalyzes a reactionthat can be measured, by measuring reaction rates. All such methods areknown in the art and can be used. Where target transthyretin RNA levelsare to be measured, art-recognized methods for detecting RNA levels canbe used (e.g., RT-PCR, Northern Blotting, etc.). In targetingtransthyretin RNAs with the dsRNA agents of the instant invention, it isalso anticipated that measurement of the efficacy of a dsRNA agent inreducing levels of transthyretin RNA or protein in a subject, tissue, incells, either in vitro or in vivo, or in cell extracts can also be usedto determine the extent of reduction of transthyretin-associatedphenotypes (e.g., disease or disorders, e.g., cancer or tumor formation,growth, metastasis, spread, etc.). The above measurements can be made oncells, cell extracts, tissues, tissue extracts or other suitable sourcematerial.

The determination of whether the expression of a transthyretin RNA hasbeen reduced can be by a suitable method that can reliably detectchanges in RNA levels. Typically, the determination is made byintroducing into the environment of a cell undigested dsRNA such that atleast a portion of that dsRNA agent enters the cytoplasm, and thenmeasuring the level of the target RNA. The same measurement is made onidentical untreated cells and the results obtained from each measurementare compared.

The dsRNA agent can be formulated as a pharmaceutical composition whichcomprises a pharmacologically effective amount of a dsRNA agent andpharmaceutically acceptable carrier. A pharmacologically ortherapeutically effective amount refers to that amount of a dsRNA agenteffective to produce the intended pharmacological, therapeutic orpreventive result. The phrases “pharmacologically effective amount” and“therapeutically effective amount” or simply “effective amount” refer tothat amount of an RNA effective to produce the intended pharmacological,therapeutic or preventive result. For example, if a given clinicaltreatment is considered effective when there is at least a 20% reductionin a measurable parameter associated with a disease or disorder, atherapeutically effective amount of a drug for the treatment of thatdisease or disorder is the amount necessary to effect at least a 20%reduction in that parameter.

Suitably formulated pharmaceutical compositions of this invention can beadministered by means known in the art such as by parenteral routes,including intravenous, intramuscular, intraperitoneal, subcutaneous,transdermal, airway (aerosol), rectal, vaginal and topical (includingbuccal and sublingual) administration. In some embodiments, thepharmaceutical compositions are administered by intravenous orintraparenteral infusion or injection.

In general, a suitable dosage unit of dsRNA will be in the range of0.001 to 0.25 milligrams per kilogram body weight of the recipient perday, or in the range of 0.01 to 20 micrograms per kilogram body weightper day, or in the range of 0.001 to 5 micrograms per kilogram of bodyweight per day, or in the range of 1 to 500 nanograms per kilogram ofbody weight per day, or in the range of 0.01 to 10 micrograms perkilogram body weight per day, or in the range of 0.10 to 5 microgramsper kilogram body weight per day, or in the range of 0.1 to 2.5micrograms per kilogram body weight per day. A pharmaceuticalcomposition comprising the dsRNA can be administered once daily.However, the therapeutic agent may also be dosed in dosage unitscontaining two, three, four, five, six or more sub-doses administered atappropriate intervals throughout the day. In that case, the dsRNAcontained in each sub-dose must be correspondingly smaller in order toachieve the total daily dosage unit. The dosage unit can also becompounded for a single dose over several days, e.g., using aconventional sustained release formulation which provides sustained andconsistent release of the dsRNA over a several day period. Sustainedrelease formulations are well known in the art. In this embodiment, thedosage unit contains a corresponding multiple of the daily dose.

Regardless of the formulation, the pharmaceutical composition mustcontain dsRNA in a quantity sufficient to inhibit expression of thetarget gene in the animal or human being treated. The composition can becompounded in such a way that the sum of the multiple units of dsRNAtogether contain a sufficient dose.

Data can be obtained from cell culture assays and animal studies toformulate a suitable dosage range for humans. The dosage of compositionsof the invention lies within a range of circulating concentrations thatinclude the ED₅₀ (as determined by known methods) with little or notoxicity. The dosage may vary within this range depending upon thedosage form employed and the route of administration utilized. For acompound used in the method of the invention, the therapeuticallyeffective dose can be estimated initially from cell culture assays. Adose may be formulated in animal models to achieve a circulating plasmaconcentration range of the compound that includes the IC₅₀ (i.e., theconcentration of the test compound which achieves a half-maximalinhibition of symptoms) as determined in cell culture. Such informationcan be used to more accurately determine useful doses in humans.

Levels of dsRNA in plasma may be measured by standard methods, forexample, by high performance liquid chromatography.

The pharmaceutical compositions can be included in a kit, container,pack, or dispenser together with instructions for administration.

Methods of Treatment

The present invention provides for both prophylactic and therapeuticmethods of treating a subject at risk of (or susceptible to) a diseaseor disorder caused, in whole or in part, by transthyretin (e.g.,misregulation and/or elevation of transthyretin transcript and/ortransthyretin protein levels), or treatable via selective targeting oftransthyretin.

“Treatment”, or “treating” as used herein, is defined as the applicationor administration of a therapeutic agent (e.g., a dsRNA agent or vectoror transgene encoding same) to a patient, or application oradministration of a therapeutic agent to an isolated tissue or cell linefrom a patient, who has the disease or disorder, a symptom of disease ordisorder or a predisposition toward a disease or disorder, with thepurpose to cure, heal, alleviate, relieve, alter, remedy, ameliorate,improve or affect the disease or disorder, the symptoms of the diseaseor disorder, or the predisposition toward disease.

In one aspect, the invention provides a method for preventing in asubject, a disease or disorder as described above (including, e.g.,prevention of the commencement of transforming events within a subjectvia inhibition of transthyretin expression), by administering to thesubject a therapeutic agent (e.g., a dsRNA agent or vector or transgeneencoding same). Subjects at risk for the disease can be identified by,for example, one or a combination of diagnostic or prognostic assays asdescribed herein. Administration of a prophylactic agent can occur priorto the detection of, e.g., cancer in a subject, or the manifestation ofsymptoms characteristic of the disease or disorder, such that thedisease or disorder is prevented or, alternatively, delayed in itsprogression.

Another aspect of the invention pertains to methods of treating subjectstherapeutically, i.e., altering the onset of symptoms of the disease ordisorder. These methods can be performed in vitro (e.g., by culturingthe cell with the dsRNA agent) or, alternatively, in vivo (e.g., byadministering the dsRNA agent to a subject).

With regards to both prophylactic and therapeutic methods of treatment,such treatments may be specifically tailored or modified, based onknowledge obtained from the field of pharmacogenomics.“Pharmacogenomics”, as used herein, refers to the application ofgenomics technologies such as gene sequencing, statistical genetics, andgene expression analysis to drugs in clinical development and on themarket. More specifically, the term refers the study of how a patient'sgenes determine his or her response to a drug (e.g., a patient's “drugresponse phenotype”, or “drug response genotype”). Thus, another aspectof the invention provides methods for tailoring an individual'sprophylactic or therapeutic treatment with either the targettransthyretin RNA molecules of the present invention or targettransthyretin RNA modulators according to that individual's drugresponse genotype. Pharmacogenomics allows a clinician or physician totarget prophylactic or therapeutic treatments to patients who will mostbenefit from the treatment and to avoid treatment of patients who willexperience toxic drug-related side effects.

Therapeutic agents can be tested in a selected animal model. Forexample, a dsRNA agent (or expression vector or transgene encoding same)as described herein can be used in an animal model to determine theefficacy, toxicity, or side effects of treatment with said agent.Alternatively, an agent (e.g., a therapeutic agent) can be used in ananimal model to determine the mechanism of action of such an agent.

Models Useful to Evaluate the Down-Regulation of Transthyretin mRNALevels and Expression

Cell Culture

The dsRNA agents of the invention can be tested for cleavage activity invivo, for example, using the following procedure. The nucleotidesequences within the transthyretin cDNA targeted by the dsRNA agents ofthe invention are shown in the above transthyretin sequences.

The dsRNA reagents of the invention can be tested in cell culture usingHuh7 or other mammalian cells (e.g., human cell lines Hep3B, HepG2,DU145, Calu3, SW480, T84, PL45, etc., and mouse cell lines AML12,Neuro2a, etc.) to determine the extent of transthyretin RNA andtransthyretin protein inhibition. In certain embodiments, DsiRNAreagents (e.g., see FIG. 1, and above-recited structures) are selectedagainst the transthyretin target as described herein. Transthyretin RNAinhibition is measured after delivery of these reagents by a suitabletransfection agent to, for example, cultured Huh7 cells or othertransformed or non-transformed mammalian cells in culture. Relativeamounts of target transthyretin RNA are measured versus HPRT1, actin orother appropriate control using real-time PCR monitoring ofamplification (e.g., ABI 7700 TAQMAN®). A comparison is made to theactivity of oligonucleotide sequences made to unrelated targets or to arandomized DsiRNA control with the same overall length and chemistry, orsimply to appropriate vehicle-treated or untreated controls. Primary andsecondary lead reagents are chosen for the target and optimizationperformed.

TAQMAN® (Real-Time PCR Monitoring ofAmplification) and LightcyclerQuantification of mRNA

Total RNA is prepared from cells following DsiRNA delivery, for example,using Ambion Rnaqueous 4-PCR purification kit for large scaleextractions, or Promega SV96 for 96-well assays. For Tagman analysis,dual-labeled probes are synthesized with, for example, the reporter dyesFAM or VIC covalently linked at the 5′-end and the quencher dye TAMRAconjugated to the 3-end. PCR amplifications are performed on, forexample, an ABI PRISM 7700 Sequence detector using 50 uL reactionsconsisting of 10 uL total RNA, 100 nM forward primer, 100 mM reverseprimer, 100 nM probe, 1 xTaqMan PCR reaction buffer (PE-AppliedBiosystems), 5.5 mM MgCl2, 100 uM each dATP, dCTP, dGTP and dTTP, 0.2 URNase Inhibitor (Promega), 0.025 U AmpliTaq Gold (PE-Applied Biosystems)and 0.2 U M-MLV Reverse Transcriptase (Promega). The thermal cyclingconditions can consist of 30 minutes at 48° C., 10 minutes at 95° C.,followed by 40 cycles of 15 seconds at 95° C. and 1 minute at 60° C.Quantitation of target transthyretin mRNA level is determined relativeto standards generated from serially diluted total cellular RNA (300,100, 30, 10 ng/rxn) and normalizing to, for example, HPRT1 mRNA ineither parallel or same tube TaqMan reactions.

Western Blotting

Cellular protein extracts can be prepared using a standard micropreparation technique (for example using RIPA buffer), or preferably, byextracting nuclear proteins by a method such as the NE-PER Nuclear andCytoplasmic Extraction kit (Thermo-Fisher Scientific). Cellular proteinextracts are run on Tris-Glycine polyacrylamide gel and transferred ontomembranes. Non-specific binding can be blocked by incubation, forexample, with 5% non-fat milk for 1 hour followed by primary antibodyfor 16 hours at 4° C. Following washes, the secondary antibody isapplied, for example (1:10,000 dilution) for 1 hour at room temperatureand the signal detected on a VersaDoc imaging system

In several cell culture systems, cationic lipids have been shown toenhance the bioavailability of oligonucleotides to cells in culture(Bennet, et al., 1992, Mol. Pharmacology, 41, 1023-1033). In oneembodiment, dsRNA molecules of the invention are complexed with cationiclipids for cell culture experiments. dsRNA and cationic lipid mixturesare prepared in serum-free OptimMEM (InVitrogen) immediately prior toaddition to the cells. OptiMEM is warmed to room temperature (about20-25° C.) and cationic lipid is added to the final desiredconcentration. dsRNA molecules are added to OptiMEM to the desiredconcentration and the solution is added to the diluted dsRNA andincubated for 15 minutes at room temperature. In dose responseexperiments, the RNA complex is serially diluted into OptiMEM prior toaddition of the cationic lipid.

Animal Models

The efficacy of anti-transthyretin dsRNA agents may be evaluated in ananimal model. Animal models of amyloidosis and/or liver diseases,conditions, or disorders as are known in the art can be used forevaluation of the efficacy, potency, toxicity, etc. ofanti-transthyretin dsRNAs. Exemplary animals model oftransthyretin-induced amyloidosis include transgenic mice that expresshuman TTR Va130Met, which recapitulates the human amyloidosis in atransgenic mouse (the behavior of such models also suggest theemployment of doxycycline and TUDCA with anti-transthyretin dsRNAs intreatment of amyloidosis (Cardoso I et al. Journal of TranslationalMedicine 8:74). Such animal models may be used as a source cells ortissue for assays of the compositions of the invention. Such models canalso be used or adapted for use for pre-clinical evaluation of theefficacy of dsRNA compositions of the invention in modulatingtransthyretin gene expression toward therapeutic use.

Such models and/or wild-type mice can be used in evaluating the efficacyof dsRNA molecules of the invention to inhibit transthyretin levels,expression, development of transthyretin-associated phenotypes, diseasesor disorders, etc. These models, wild-type mice and/or other models cansimilarly be used to evaluate the safety/toxicity and efficacy of dsRNAmolecules of the invention in a pre-clinical setting.

Specific examples of animal model systems useful for evaluation of thetransthyretin-targeting dsRNAs of the invention include wild-type miceand transgenic TTR Val30Met mutant model mice. In an exemplary in vivoexperiment, dsRNAs of the invention are tail vein injected into suchmouse models at doses ranging from 1 to 10 mg/kg or, alternatively,repeated doses are administered at single-dose IC₅₀ levels, and organsamples (e.g., liver, but may also include prostate, kidney, lung,pancreas, colon, skin, spleen, bone marrow, lymph nodes, mammary fatpad, etc.) are harvested 24 hours after administration of the finaldose. Such organs are then evaluated for mouse and/or humantransthyretin levels, depending upon the model used. Duration of actioncan also be examined at, e.g., 1, 4, 7, 14, 21 or more days after finaldsRNA administration.

The practice of the present invention employs, unless otherwiseindicated, conventional techniques of chemistry, molecular biology,microbiology, recombinant DNA, genetics, immunology, cell biology, cellculture and transgenic biology, which are within the skill of the art.See, e.g., Maniatis et al., 1982, Molecular Cloning (Cold Spring HarborLaboratory Press, Cold Spring Harbor, N.Y.); Sambrook et al., 1989,Molecular Cloning, 2nd Ed. (Cold Spring Harbor Laboratory Press, ColdSpring Harbor, N.Y.); Sambrook and Russell, 2001, Molecular Cloning, 3rdEd. (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.);Ausubel et al., 1992), Current Protocols in Molecular Biology (JohnWiley & Sons, including periodic updates); Glover, 1985, DNA Cloning(IRL Press, Oxford); Anand, 1992; Guthrie and Fink, 1991; Harlow andLane, 1988, Antibodies, (Cold Spring Harbor Laboratory Press, ColdSpring Harbor, N.Y.); Jakoby and Pastan, 1979; Nucleic AcidHybridization (B. D. Hames & S. J. Higgins eds. 1984); Transcription AndTranslation (B. D. Hames & S. J. Higgins eds. 1984); Culture Of AnimalCells (R. I. Freshney, Alan R. Liss, Inc., 1987); Immobilized Cells AndEnzymes (IRL Press, 1986); B. Perbal, A Practical Guide To MolecularCloning (1984); the treatise, Methods In Enzymology (Academic Press,Inc., N.Y.); Gene Transfer Vectors For Mammalian Cells (J. H. Miller andM. P. Calos eds., 1987, Cold Spring Harbor Laboratory); Methods InEnzymology, Vols. 154 and 155 (Wu et al. eds.), Immunochemical MethodsIn Cell And Molecular Biology (Mayer and Walker, eds., Academic Press,London, 1987); Handbook Of Experimental Immunology, Volumes I-IV (D. M.Weir and C. C. Blackwell, eds., 1986); Riott, Essential Immunology, 6thEdition, Blackwell Scientific Publications, Oxford, 1988; Hogan et al.,Manipulating the Mouse Embryo, (Cold Spring Harbor Laboratory Press,Cold Spring Harbor, N.Y., 1986); Westerfield, M., The zebrafish book. Aguide for the laboratory use of zebrafish (Danio rerio), (4th Ed., Univ.of Oregon Press, Eugene, 2000).

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Although methods and materialssimilar or equivalent to those described herein can be used in thepractice or testing of the present invention, suitable methods andmaterials are described below. All publications, patent applications,patents, and other references mentioned herein are incorporated byreference in their entirety. In case of conflict, the presentspecification, including definitions, will control. In addition, thematerials, methods, and examples are illustrative only and not intendedto be limiting.

EXAMPLES

The present invention is described by reference to the followingExamples, which are offered by way of illustration and are not intendedto limit the invention in any manner. Standard techniques well known inthe art or the techniques specifically described below were utilized.

Example 1: Preparation of Double-Stranded RNA Oligonucleotides

Oligonucleotide Synthesis and Purification

DsiRNA molecules were designed to interact with various sites in the RNAmessage, for example, target sequences within the RNA sequencesdescribed herein. In presently exemplified agents, 384 human targettransthyretin sequences were selected for evaluation (a selection of the384 human target transthyretin sites were predicted to be conserved withcorresponding sites in the mouse transthyretin transcript sequence). Thesequences of one strand of the DsiRNA molecules were complementary tothe target transthyretin site sequences described above. The DsiRNAmolecules were chemically synthesized using methods described herein.Generally, DsiRNA constructs were synthesized using solid phaseoligonucleotide synthesis methods as described for 19-23 mer siRNAs (seefor example Usman et al., U.S. Pat. Nos. 5,804,683; 5,831,071;5,998,203; 6,117,657; 6,353,098; 6,362,323; 6,437,117; 6,469,158;Scaringe et al., U.S. Pat. Nos. 6,111,086; 6,008,400; 6,111,086).

Individual RNA strands were synthesized and HPLC purified according tostandard methods (Integrated DNA Technologies, Coralville, Iowa). Forexample, RNA oligonucleotides were synthesized using solid phasephosphoramidite chemistry, deprotected and desalted on NAP-5 columns(Amersham Pharmacia Biotech, Piscataway, N.J.) using standard techniques(Damha and Olgivie, 1993, Methods Mol Biol 20: 81-114; Wincott et al.,1995, Nucleic Acids Res 23: 2677-84). The oligomers were purified usingion-exchange high performance liquid chromatography (IE-HPLC) on anAmersham Source 15Q column (1.0 cm×25 cm; Amersham Pharmacia Biotech,Piscataway, N.J.) using a 15 min step-linear gradient. The gradientvaried from 90:10 Buffers A:B to 52:48 Buffers A:B, where Buffer A was100 mM Tris pH 8.5 and Buffer B was 100 mM Tris pH 8.5, 1 M NaCl.Samples were monitored at 260 nm and peaks corresponding to thefull-length oligonucleotide species were collected, pooled, desalted onNAP-5 columns, and lyophilized.

The purity of each oligomer was determined by capillary electrophoresis(CE) on a Beckman PACE 5000 (Beckman Coulter, Inc., Fullerton, Calif.).The CE capillaries had a 100 inn inner diameter and contained ssDNA 100RGel (Beckman-Coulter). Typically, about 0.6 nmole of oligonucleotide wasinjected into a capillary, run in an electric field of 444 V/cm anddetected by UV absorbance at 260 nm. Denaturing Tris-Borate-7 M-urearunning buffer was purchased from Beckman-Coulter. Oligoribonucleotideswere obtained that were at least 90% pure as assessed by CE for use inexperiments described below. Compound identity was verified bymatrix-assisted laser desorption ionization time-of-flight (MALDI-TOF)mass spectroscopy on a Voyager DE™ Biospectometry Work Station (AppliedBiosystems, Foster City, Calif.) following the manufacturer'srecommended protocol. Relative molecular masses of all oligomers wereobtained, often within 0.2% of expected molecular mass.

Preparation of Duplexes

Single-stranded RNA (ssRNA) oligomers were resuspended, e.g., at 100 μMconcentration in duplex buffer consisting of 100 mM potassium acetate,30 mM HEPES, pH 7.5. Complementary sense and antisense strands weremixed in equal molar amounts to yield a final solution of, e.g., 50 μMduplex. Samples were heated to 100° C. for 5′ in RNA buffer (IDT) andallowed to cool to room temperature before use. Double-stranded RNA(dsRNA) oligomers were stored at −20° C. Single-stranded RNA oligomerswere stored lyophilized or in nuclease-free water at −80° C.

Nomenclature

For consistency, the following nomenclature has been employed in theinstant specification. Names given to duplexes indicate the length ofthe oligomers and the presence or absence of overhangs. A “25/27” is anasymmetric duplex having a 25 base sense strand and a 27 base antisensestrand with a 2-base 3′-overhang. A “27/25” is an asymmetric duplexhaving a 27 base sense strand and a 25 base antisense strand.

Cell Culture and RNA Transfection

Huh7 cells were obtained and maintained in DMEM (HyClone) supplementedwith 10% fetal bovine serum (HyClone) at 37° C. under 5% CO2. For RNAtransfections, cells were transfected with DsiRNAs at a finalconcentration of 1 nM, 0.1 nM or 0.03 nM using Lipofectamine™ RNAiMAX(Invitrogen) and following manufacturer's instructions. Briefly, for 0.1nM transfections, e.g., of Example 3 below, an aliquot of stock solutionof each DsiRNA was mixed with Opti-MEM I (Invitrogen) and Lipofectamine™RNAiMAX to reach a volume of 150 μL (with 0.3 nM DsiRNA). The resulting150 μL mix was incubated for 20 min at RT to allow DsiRNA:Lipofectamine™RNAiMAX complexes to form. Meanwhile, target cells were trypsinized andresuspended in medium. At the end of the 20 min of complexation, 50 uLof the DsiRNA:RNAiMAX mixture was added per well into triplicate wellsof 96 well plates. Finally, 100 μL of the cell suspension was added toeach well (final volume 150 μL) and plates were placed into theincubator for 24 hours.

Assessment of Transthyretin Inhibition

Transthyretin target gene knockdown was determined by qRT-PCR, withvalues normalized to HPRT and SFRS9 housekeeping genes, and totransfections with control DsiRNAs and/or mock transfection controls.

RNA Isolation and Analysis

Media was aspirated, and total RNA was extracted using the SV96 kit(Promega). Total RNA was reverse-transcribed using SuperscriptII, OligodT, and random hexamers following manufacturer's instructions.Typically, the resulting cDNA was analyzed by qPCR using primers andprobes specific for both the transthyretin gene and for the human genesHPRT-1 and SFRS9. An ABI 7700 was used for the amplification reactions.Each sample was tested in triplicate. Relative transthyretin RNA levelswere normalized to HPRT1 and SFRS9 RNA levels and compared with RNAlevels obtained in transfection control samples.

Example 2: DsiRNA Inhibition of Transthyretin

DsiRNA molecules targeting transthyretin were designed and synthesizedas described above and tested in human Huh7 cells (alternatively, HepG2or other human cells could have been used) for inhibitory efficacy. Fortransfection, annealed DsiRNAs were mixed with the transfection reagent(Lipofectamine™ RNAiMAX, Invitrogen) and incubated for 20 minutes atroom temperature. The Huh7 (human) or AML12 (mouse) cells(alternatively, mouse Hepal-6 or other mouse cells could have been used)were trypsinized, resuspended in media, and added to wells (100 μL perwell) to give a final DsiRNA concentration of 1 nM in a volume of 150Each DsiRNA transfection mixture was added to 3 wells for triplicateDsiRNA treatments. Cells were incubated at 37° C. for 24 hours in thecontinued presence of the DsiRNA transfection mixture. At 24 hours, RNAwas prepared from each well of treated cells. The supernatants with thetransfection mixtures were first removed and discarded, then the cellswere lysed and RNA was prepared from each well.

Target transthyretin RNA levels following treatment were evaluated byqRT-PCR for the transthyretin target gene, with values normalized tothose obtained for controls. Triplicate data was averaged and the %error was determined for each treatment. Normalized data were bothtablulated and graphed, and the reduction of target mRNA by activeDsiRNAs in comparison to controls was determined (see Table 7 below andFIGS. 2A to 2D).

TABLE 7 Transthyretin Inhibitory Efficacy of DsiRNAs Assayed at 1 nM inHuman Huh7 and Mouse AML12 Cells Human - Huh7 Mouse - AML12 NormalizedHPRT/Rpl23; vs Normalized HPRT/Rpl23; vs NC1, NC5, NC7 NC1, NC5, NC7 Hs67-196 Hs 67-196 Mm 340-469 Mm 340-469 Duplex Mm Macaque* (FAM) Assay(FAM) Assay (FAM) Assay (FAM) Assay Name Location Location % Remaining %Remaining % Remaining % Remaining TTR-27 79  94.1 ± 17.1 102.3 ± 3.2 30.5 ± 11.8  34.1 ± 1.5 TTR-28 80 126.7 ± 5  97.7 ± 5.1  58.6 ± 6.7 65.7 ± 6.4 TTR-29 81 131.6 ± 3.8   104 ± 5.1  46.1 ± 4.4  55.1 ± 4.2TTR-30 82 111.6 ± 0.9   87 ± 2.2 100.8 ± 5.7 109.9 ± 8.4 TTR-31 83 106.8± 10.4  89.3 ± 3.5  68.3 ± 5.4  68.5 ± 5.5 TTR-32 84 112.6 ± 6.1  75.9 ±5.2  70.1 ± 8.3  66.4 ± 6.4 TTR-33 85 121.4 ± 5.1  87.3 ± 4.9 102.8 ±6.8 102.8 ± 10.1 TTR-34 86 117.7 ± 7.2  86.3 ± 1.8  82.9 ± 4  75.4 ± 3.2TTR-35 87  84.5 ± 8.9   100 ± 4.3  85.8 ± 3.3  89.4 ± 5.8 TTR-36 88121.6 ± 14.8   98 ± 4.3 108.3 ± 3.6 110.9 ± 6.9 TTR-37 89 102.4 ± 2 80.9 ± 2.4 107.3 ± 5.3 114.1 ± 2 TTR-38 90 102.7 ± 9.6  77.5 ± 4.1103.6 ± 4.4 112.8 ± 4.2 TTR-39 91 103.3 ± 2.8  77.9 ± 5.2   98 ± 4.4 86.6 ± 5.9 TTR-40 92 113.8 ± 11.6  75.3 ± 4 106.4 ± 2 106.7 ± 6.3TTR-41 93  91.6 ± 14.4  67.3 ± 7 104.5 ± 1.9 104.5 ± 6.5 TTR-43 110.9 ±3.8 110.1 ± 2.3 TTR-44   98 ± 2.4 101.8 ± 1.1 TTR-46   103 ± 2.8  97.1 ±1.5 TTR-47  92.9 ± 5  98.4 ± 5.3 TTR-59  95.2 ± 9.3  98.3 ± 6 TTR-84 58.6 ± 2.4 100.3 ± 9.1 TTR-87  33.4 ± N/A 102.7 ± N/A TTR-88  33.4 ±6.6 104.5 ± 4 TTR-89  48.5 ± 7.7  96.5 ± 5.8 TTR-90  44.8 ± 5.8 106.9 ±5.3 TTR-92  66.1 ± 11.4 103.6 ± 2.8 TTR-126  38.9 ± 18 106.1 ± 4.1TTR-127  29.8 ± 11.5  96.9 ± 3 TTR-128  8.9 ± 25.8  89.2 ± 5.4 TTR-129 7.5 ± 27.8  50.6 ± 10.2 TTR-130  4.8 ± 15.2   45 ± 5.2 TTR-131  6.6 ±20.5  30.9 ± 9.9 TTR-132  10.7 ± 11.5   21 ± 9 TTR-134   32 ± 11.8  32.8± 5.8 TTR-135  30.3 ± 13  38.6 ± 9.8 TTR-150 70  7.2 ± 35.1  10.4 ± 4.7108.9 ± 3.9 106.8 ± 10 TTR-151 71  34.6 ± 13.9   27 ± 8.3 109.8 ± 2106.1 ± 8.6 TTR-152 72  0.9 ± 57.3  3.5 ± 5.4 109.3 ± 7.3 136.7 ± 3.7TTR-153 73  0.8 ± 65.4  3.9 ± 7.8 132.7 ± 7.5 119.1 ± 4.2 TTR-154 74   7 ± 2.2  7.3 ± 5.5 114.8 ± 3.3 116.7 ± 3.9 TTR-155 75  2.1 ± 53.9 3.7 ± 3.9 106.1 ± 2.5 111.2 ± 1.6 TTR-156 76  3.1 ± 19.7  3.3 ± 5.3105.2 ± 8  97.6 ± 11.3 TTR-157 77  1.7 ± 62  5.3 ± 5.1 TTR-158 78  1.5 ±73.7    3 ± 7.8 TTR-159 79  1.5 ± 58.5  3.9 ± 11.5 TTR-160 80  2.2 ±20.1  4.3 ± 7.9 TTR-161 81  1.6 ± 50.6  5.3 ± 7 TTR-162 82  5.9 ± 48.7 14.2 ± 5.2 TTR-163 83  55.4 ± 11  63.5 ± 8.4 TTR-164 84  0.8 ± 52.1 7.3 ± 5 TTR-165 85  9.3 ± 28  20.3 ± 3.6 TTR-186   15 ± 16.4  15.4 ±8.3 TTR-187  8.9 ± 32.8  9.6 ± 11.5 TTR-234  8.3 ± 11.9  5.3 ± 1.4TTR-238 158  4.3 ± 50.7  2.8 ± 9.7 TTR-239 159  2.8 ± 100  6.5 ± 11.9TTR-240 160  0.7 ± 100  3.1 ± 2.1 TTR-241 161  15.8 ± 29.3  8.1 ± 10.3TTR-242 162  1.9 ± 100  1.4 ± 5 TTR-243 163    9 ± 38.9  7.1 ± 6.8TTR-244 164  3.6 ± 100  2.2 ± 4.8 TTR-245 165  0.3 ± 100  1.7 ± 7.6TTR-246 166    2 ± 72.4  4.7 ± 6.4 TTR-247 167  21.9 ± 10.8  9.8 ± 5.7TTR-248 301  4.7 ± 7.3  3.6 ± 5.8 118.7 ± 2.1 107.2 ± 3.7 TTR-249 302 2.3 ± 19.4  2.9 ± 13.3   107 ± 6.2 123.9 ± 20.3 TTR-250 170  7.3 ± 41.1 3.4 ± 6.5 TTR-251 171  16.3 ± 21.5  15.4 ± 5.4 TTR-252 172    0 ± N/A 2.6 ± 2.5 TTR-253 173  17.2 ± 35.1  11.6 ± 8.2 TTR-254 174  3.6 ± 55.1 7.5 ± 5.7 TTR-255 175  1.5 ± 42.2  2.5 ± 10.3 TTR-256 176  7.7 ± 51.3 9.1 ± 7 TTR-257 177  0.6 ± 100  2.2 ± 3.1 TTR-258 178  2.8 ± 79.2  4.5± 20.1 TTR-346 266  4.3 ± 31  6.7 ± 2.1 TTR-347 267  7.3 ± 23  6.5 ± 6.5TTR-348 268  80.5 ± 5.9  68.6 ± 5.5 TTR-349 269  33.1 ± 7.6  25.4 ± 4.9TTR-350 270   30 ± 4.3   34 ± 1.8 TTR-351 271  85.6 ± 12.9  84.6 ± 5.9TTR-352 272  23.4 ± 14.3  21.3 ± 3.2 TTR-353 273  79.8 ± 6.7  82.2 ±10.4 TTR-354 274  15.7 ± 20.4  9.9 ± 4.7 TTR-355 275  4.4 ± 70  8.4 ±4.7 TTR-356 276   13 ± 17.9  7.9 ± 2.6 TTR-357 277  3.9 ± 44.2  3.8 ±3.4 TTR-358 278  4.8 ± 29.8  8.1 ± 5.7 TTR-359 279  47.2 ± 4.7  48.5 ±5.6 TTR-360 280  11.4 ± 10.4  8.3 ± 1 TTR-361 281   20 ± 5.7  20.2 ± 4.8TTR-381 301   19 ± 15.8  27.8 ± 5.5 TTR-382 302   68 ± 13.7  55.1 ± 2.5TTR-383 303  3.4 ± 67.8  4.4 ± 2.9 TTR-384 304  24.8 ± 25.1  14.8 ± 2.5TTR-385 305  31.6 ± 5.2  25.8 ± 3.7 TTR-386 306  63.7 ± 6.9  57.8 ± 4.5TTR-387 307  36.8 ± 4.1  26.6 ± 15.4 TTR-388 308   62 ± 7.1  55.1 ± 7TTR-389 309   60 ± 8.8  54.5 ± 7.2 TTR-390 310  17.8 ± 45.5  10.9 ± 23.6TTR-391 311  36.4 ± 5.3  29.5 ± 7.3 TTR-392 312   30 ± 20.7  18.7 ± 16.7TTR-393 313  28.7 ± 6.6  22.6 ± 5.7 TTR-394 314  21.7 ± 3.1   18 ± 3.3TTR-395 315  49.3 ± 7.5  45.4 ± 7.5 TTR-396 316  11.8 ± 24.9  12.5 ± 5.3TTR-398  35.9 ± 8  30.7 ± 6.2 TTR-399  16.8 ± 28.5  11.6 ± 12.3 TTR-400 83.3 ± 6.4  71.8 ± 8.7 TTR-401   52 ± 27  43.9 ± 20.8 TTR-402  30.5 ±29.5  29.5 ± 27.5 TTR-403  34.3 ± 29  27.7 ± 28.9 TTR-404  31.4 ± 23 33.8 ± 19.2 TTR-405  5.6 ± 15  6.2 ± 5.6 TTR-406    7 ± 5.9  9.6 ± 6.4TTR-407  13.7 ± 51.2   17 ± 10.1 TTR-408   38 ± 22  35.1 ± 12.9 TTR-409 21.9 ± 17.9  16.9 ± 9.7 TTR-410  31.2 ± 9.6  33.2 ± 7.1 TTR-411  61.7 ±6.1  46.8 ± 6.6 TTR-412  42.5 ± 12.4  32.9 ± 19.8 TTR-413  36.8 ± 6.8 26.1 ± 3.4 TTR-414  35.9 ± 13.8   37 ± 3.1 TTR-415  52.1 ± 43.9  43.8 ±46.3 TTR-416  33.1 ± 12.9  28.8 ± 11.9 TTR-417  73.3 ± 7.5   65 ± 2.6TTR-418   16 ± 10.4  16.6 ± 3.9 TTR-419   90 ± 2.1  73.7 ± 3.7 TTR-420 44.5 ± 6.4   37 ± 7.4 TTR-421   46 ± 10.8   40 ± 5.3 TTR-422  2.6 ±10.9  3.4 ± 13.1 TTR-423  4.4 ± 12.4  3.5 ± 7.5 TTR-424  4.4 ± 13.3  5.6± 10.3 TTR-425  27.7 ± 27.9  36.3 ± 21.7 TTR-426  17.7 ± 31.8  29.2 ±19.6 TTR-427  11.2 ± 16.7  15.5 ± 18 TTR-428  6.8 ± 38.1  6.7 ± 8.8TTR-429  8.3 ± 23.3    6 ± 2.6 TTR-430  4.1 ± 62.2  13.4 ± 2 TTR-431 30.1 ± 5.4  46.1 ± 2.3 TTR-432  3.6 ± 37.5  5.1 ± 2.2 TTR-433  7.7 ±42.7    5 ± 0.8 TTR-434  1.6 ± 66.9  2.8 ± 2.5 TTR-435  7.3 ± 47.3  3.4± 5.9 TTR-436  3.4 ± 26.3  5.5 ± 7.7 TTR-437   34 ± 14.5  30.9 ± 2.8TTR-439  2.6 ± 41.1  4.7 ± 12.5 TTR-440  9.1 ± 16.8  6.6 ± 5.2 TTR-462382  46.2 ± 9  42.4 ± 9.4 TTR-463 383  89.4 ± 5  70.6 ± 3.5 TTR-464 384 14.9 ± 14.3  11.3 ± 10.4 TTR-465 385  27.1 ± 12.9   20 ± 3.6 TTR-466386  17.5 ± 17.5  14.3 ± 7.9 TTR-467 387  80.8 ± 3.9  75.9 ± 1.2 TTR-468388  83.8 ± 7.1  69.6 ± 4.9 TTR-469 389  95.7 ± 1.6  92.1 ± 2.6 TTR-470390   27 ± 14.4  24.7 ± 8.4 TTR-471 391  32.7 ± 11.3  26.3 ± 5.1 TTR-472392  73.9 ± 3.3   63 ± 2.5 TTR-473 393   78 ± 2.7  69.4 ± 3.1 TTR-474394  49.4 ± 4.7  53.6 ± 4.2 TTR-482  6.6 ± 20.6  7.2 ± 8.4 TTR-483  1.8± 6.7  4.4 ± 3.7 TTR-484  0.8 ± 100  4.9 ± 6.2 TTR-485  32.1 ± 9.5  26.1± 3.9 TTR-489  4.1 ± 51.5  5.6 ± 14.1 TTR-493  7.9 ± 10.6  11.8 ± 6.2TTR-494  9.6 ± 50.3  4.9 ± 10.3 TTR-581 122.5 ± 9.1  92.4 ± 2 TTR-631 10.4 ± 81.2  3.7 ± 14.9 TTR-632  15.4 ± 16.9  2.8 ± 6.6 TTR-635    9 ±21.6  7.2 ± 17.9 TTR-636   11 ± 82.8  3.3 ± 19.3 TTR-637  2.3 ± 68.1 3.5 ± 4.4 TTR-639  12.3 ± 13.2  7.9 ± 1.7 TTR-640  2.5 ± 40.3  4.1 ±4.1 TTR-641    7 ± 57.5  3.2 ± 3.7 TTR-642  9.7 ± 17.5  6.1 ± 11.2TTR-643  0.9 ± 100  2.1 ± 12.4 TTR-644  2.9 ± 66.5  4.5 ± 2.7 TTR-645 4.1 ± 63.7  1.7 ± 9 TTR-646  2.5 ± 67.4  3.6 ± 9.7 TTR-647  7.6 ± 18 4.4 ± 6.6 TTR-648    0 ± N/A  2.3 ± 3 TTR-649  10.8 ± 40.8  4.5 ± 4.5TTR-650    0 ± N/A  1.5 ± 5 TTR-651  0.9 ± 100  1.6 ± 16.1 TTR-652  5.5± 35.9  4.7 ± 5.7 TTR-653    5 ± 7.8  2.5 ± 3.2 TTR-654  3.5 ± 50  2.9 ±1.7 TTR-655    6 ± 47.7  4.2 ± 6 TTR-656    2 ± 40.8  2.7 ± 8.9 TTR-657   1 ± 100  2.1 ± 7.6 TTR-658    8 ± 50.2  2.1 ± 2.4 TTR-659  7.3 ± 70.9 1.3 ± 6.6 TTR-660    1 ± 50.3  2.7 ± 15.5 TTR-661  9.2 ± 66  1.2 ± 7.8TTR-662  4.3 ± 67.4  2.5 ± 4.4 TTR-663  19.6 ± 14.3  15.5 ± 5.7 TTR-664 3.3 ± 58.2  2.5 ± 4.1 TTR-665  6.9 ± 38  6.7 ± 8.3 TTR-666  18.6 ± 36.8 13.2 ± 5.9 TTR-667  4.9 ± 46.9  2.3 ± 5.7 TTR-668  0.7 ± 52.5  1.3 ±22.1 TTR-669  9.3 ± 74.5  2.5 ± 14.5 TTR-670  1.8 ± 4.4  3.1 ± 12.7TTR-671  33.7 ± 18.5   30 ± 4.2 TTR-672  10.5 ± 42.7  12.5 ± 13.2TTR-673  7.5 ± 82.8  2.8 ± 6.6 TTR-674  5.6 ± 34.1  5.2 ± 8.6 TTR-675 10.9 ± 6.3  5.4 ± 7.5 TTR-676  2.4 ± 85  2.3 ± 14.4 TTR-677  10.4 ±24.1  3.6 ± 3.3 TTR-678  5.6 ± 21.8    3 ± 2.2 TTR-679  7.7 ± 38.3  4.6± 2.1 TTR-680  8.7 ± 52.1  2.3 ± 19.4 TTR-681  5.4 ± 71.2  3.3 ± 14.7TTR-682  7.4 ± 70.1  2.9 ± 14.6 TTR-683  3.7 ± 100  1.8 ± 19.8 TTR-684 0.8 ± 50.2  2.8 ± 11.6 TTR-685  2.3 ± 100  1.6 ± 12.6 TTR-686  2.9 ±50.2  2.5 ± 18.3 TTR-687  11.8 ± 27.8  7.2 ± 7.9 TTR-688  3.8 ± 57.5 8.3 ± 7.8 TTR-689  14.1 ± 33  5.7 ± 14.5 TTR-690    1 ± 57.3  1.3 ± 3.6TTR-691  2.5 ± 50  2.5 ± 7.5 TTR-692  2.1 ± 67.6  1.9 ± 12.3 TTR-693 3.9 ± 45.3  2.3 ± 5.7 TTR-694  6.5 ± 50  1.9 ± 7.8 TTR-695  6.7 ± 57.3 4.8 ± 10.1 TTR-696  5.8 ± 67    4 ± 7.7 TTR-697  9.9 ± 18.5  6.2 ± 13.9TTR-698  5.3 ± 57.3  3.5 ± 8.4 TTR-699  11.3 ± 16.6  7.8 ± 6.8 TTR-702 2.3 ± 22.4  2.9 ± 10.8 TTR-704  6.8 ± 53    3 ± 35.4 TTR-705  4.9 ±55.5  4.3 ± 3.5 TTR-706  13.6 ± 28.2  5.5 ± 7.2 TTR-707    0 ± N/A    6± 8 TTR-708  1.5 ± 100  4.2 ± 6 TTR-709  3.4 ± 100  3.4 ± 29.2 TTR-710   4 ± 62.8  7.4 ± 22.9 TTR-711  1.4 ± 100  2.5 ± 23.9 TTR-712    3 ±50.5  2.1 ± 10.4 TTR-713  5.5 ± 62  10.4 ± 11.7 TTR-714  3.1 ± 55.3  2.9± 13 TTR-716    0 ± N/A  3.4 ± 10.6 TTR-717  5.7 ± 43.2    4 ± 9 TTR-718   2 ± 60.8  2.7 ± 3.2 TTR-719  0.9 ± 100  2.8 ± 6 TTR-720  3.6 ± 54.5 2.4 ± 8 TTR-721  4.1 ± 75.5    3 ± 6.4 TTR-722    0 ± N/A  3.7 ± 5.3TTR-723    3 ± 57.4  5.3 ± 7.3 TTR-724  2.7 ± 100  12.6 ± 9.4 TTR-725 6.9 ± 53  3.2 ± 16.1 TTR-726  1.1 ± 100  2.4 ± 14.2 TTR-727  0.3 ± 100 2.1 ± 10.5 TTR-728  10.5 ± 9.9  7.4 ± 3.5 TTR-731  10.1 ± 31.9  7.4 ±2.8 TTR-732  4.2 ± 100  7.5 ± 2.4 TTR-733  13.8 ± 30.9   17 ± 3.6TTR-734   16 ± 26.9  20.3 ± 8.7 TTR-735   85 ± 8.3  76.9 ± 12.7 TTR-736 78.6 ± 6.4  75.4 ± 9.9 TTR-738  89.7 ± 10  79.8 ± 9.5 TTR-739  96.2 ±14  96.5 ± 3.7 TTR-740 121.1 ± 17.7  84.8 ± 12.7 TTR-741  93.2 ± 7.5 98.4 ± 10 TTR-742  97.4 ± 9.6 100 ± 3.6 TTR-743 101.1 ± 5.7 114.3 ± 6.4TTR-744 122.9 ± 9.4  97.1 ± 1.7 TTR-745  88.1 ± 8   74 ± 14.7 TTR-746 77.6 ± 14.1  74.5 ± 3 TTR-747   72 ± 10.1  79.8 ± 2.8 TTR-748  89.4 ±9.5  72.5 ± 2.9 TTR-749 110.8 ± 12.6  90.2 ± 10.3 TTR-750 134.5 ± 5.4112.6 ± 5.3 TTR-751  72.1 ± 16.8   96 ± 8.4 TTR-752 104.1 ± 2.8 100.6 ±7 TTR-753  94.1 ± 9.8  83.9 ± 10.7 TTR-754 106.6 ± 4   82 ± 5.8 TTR-755 85.3 ± 9.4  80.9 ± 3.7 TTR-756  92.7 ± 6.7  76.5 ± 2.5 TTR-757 109.9 ±4.8  88.3 ± 3.8 TTR-758   129 ± 3.5 115.3 ± 4.5 TTR-759  93.2 ± 3 110.3± 2.9 TTR-760 107.3 ± 2.1 103.3 ± 3.3 TTR-761  96.1 ± 3.7  96.8 ± 8TTR-762  95.2 ± 3.7  92.1 ± 4.4 TTR-763  83.7 ± 4.6  97.2 ± 3.9 TTR-764101.4 ± 4.7   105 ± 3.6 TTR-765  95.3 ± 6.8  95.6 ± 9.9 TTR-766 108.6 ±1.8 120.1 ± 1.9 TTR-767   94 ± 3.8   104 ± 1.4 TTR-768 102.8 ± 7.4  99.6± 7 TTR-769  96.9 ± 5.2  94.9 ± 7 TTR-770  94.4 ± 5.1  90.6 ± 4.3TTR-771  91.6 ± 3  95.1 ± 4.9 TTR-772 100.7 ± 4.1  82.8 ± 3.8 TTR-773 93.1 ± 2.4  89.4 ± 7.4 TTR-775 102.4 ± 3.2 109.1 ± 1.8 TTR-780  93.5 ±3.1  99.5 ± 7.8 TTR-781 103.8 ± 1.8  93.6 ± 3 TTR-784 100.9 ± 4.4  84.1± 6.1 TTR-805  88.3 ± 3.8  81.8 ± 6 TTR-806  87.3 ± 6.3  86.8 ± 6.8TTR-807  95.7 ± 2  91.4 ± 4.2 TTR-808  87.2 ± 2.5  86.3 ± 3 TTR-809118.6 ± 5 126.5 ± 3.4 TTR-810  81.7 ± 7.2 110.6 ± 6.4 TTR-811 103.4 ±4.2 102.3 ± 3.6 TTR-812  89.5 ± 4.9  94.1 ± 2.6 TTR-813  89.1 ± 8.6   99± 4.7 TTR-814  83.1 ± 2.9  94.7 ± 3 TTR-815  90.9 ± 7.2  87.5 ± 8.4TTR-816  94.3 ± 5.1  93.5 ± 3.8 TTR-817  94.2 ± 3.8  97.4 ± 2.9 TTR-818 86.3 ± 5.7  99.2 ± 3.8 TTR-819  79.9 ± 1.2  83.1 ± 3.2 TTR-821  86.7 ±6.3  91.4 ± 4 TTR-822  84.3 ± 2.6  89.8 ± 1.3 TTR-823   92 ± 3.4  91.7 ±3.8 TTR-824  91.5 ± 2.2  94.9 ± 1.8 TTR-825  92.2 ± 6.8  94.4 ± 5.8TTR-826 110.8 ± 4.3   109 ± 4.1 TTR-827  73.8 ± 5.4  89.3 ± 8.5 TTR-828 99.1 ± 4 100.2 ± 3.6 TTR-829   91 ± 3.3  91.8 ± 1.3 TTR-830  93.9 ±14.8  97.3 ± 5.5 TTR-831  88.2 ± 3  95.6 ± 0.6 TTR-832  90.8 ± 2.9  88.9± 4.4 TTR-833  92.3 ± 2  88.6 ± 2 TTR-834 106.2 ± 2.8 106.3 ± 3.4TTR-835  87.5 ± 4.9 102.5 ± 5 TTR-869  84.8 ± 6  94.8 ± 6 TTR-870  90.9± 2.4  86.7 ± 2.4 TTR-873  83.1 ± 3.2  91.3 ± 1.8 TTR-874  86.3 ± 7.2 91.5 ± 6.1 TTR-875 107.4 ± 6.5 101.9 ± 14.3 TTR-876  90.9 ± 4  78.2 ±7.7 TTR-877  88.7 ± 1.9  87.7 ± 3.3 TTR-878  92.9 ± 2.3  99.5 ± 2.3TTR-879  89.1 ± 2.8  92.3 ± 6.5 TTR-880  89.4 ± 9.5  84.2 ± 4.4 TTR-881 93.6 ± 9.5  88.8 ± 3 TTR-882  95.8 ± 5  88.4 ± 4.6 TTR-883  98.9 ± 6.3 79.6 ± 6.1 TTR-884 111.9 ± 4.4  87.8 ± 0.6 TTR-885  91.5 ± 13.4  88.7 ±1.9 TTR-886  95.5 ± 16.2 101.6 ± 13.9 TTR-887 110.6 ± 7.3   110 ± 7.6TTR-888  97.1 ± 6.2  91.7 ± 1.9 TTR-889   99 ± 3.2  85.1 ± 3 TTR-890 89.3 ± 9  93.3 ± 3.2 TTR-891  89.8 ± 6.3  84.8 ± 4.1 TTR-892  93.8 ±6.4  82.2 ± 4 TTR-893 114.2 ± 9.8 100.2 ± 3.4 TTR-894  73.7 ± 2.3  83.8± 2.5 TTR-895   91 ± 4  86.4 ± 2.4 TTR-896  91.8 ± 8  86.5 ± 3.1 TTR-897 95.5 ± 8.5  89.1 ± 3.5 TTR-898   101 ± 3.1  97.5 ± 2.6 TTR-899  99.7 ±3.5  89.4 ± 3 TTR-900  88.7 ± 4.1  86.4 ± 1.9 TTR-901  91.1 ± 8.1  97.4± 1.9 TTR-902  72.3 ± 3.6  78.7 ± 5.6 TTR-903   102 ± 5.4  93.2 ± 2.4TTR-904  98.7 ± 6  87.9 ± 4 TTR-905  90.5 ± 2.9  89.7 ± 3.9 TTR-906 95.8 ± 4.1  91.8 ± 1.2 TTR-908   101 ± 4.4  90.7 ± 2.8 TTR-909  93.9 ±2.2  82.2 ± 1.7 TTR-911  90.2 ± 5.3  85.8 ± 1.4 TTR-912  79.1 ± 6.7 83.2 ± 3.8 TTR-913  92.2 ± 8.2  87.7 ± 1.7 TTR-914   103 ± 6.6  95.3 ±5.6 TTR-915  98.8 ± 8.8  86.2 ± 3.5 TTR-916  99.5 ± 7.4  95.4 ± 0.7TTR-917  99.3 ± 9.2  92.4 ± 3.5 TTR-918 101.8 ± 6.5  93.1 ± 7.8 TTR-919 98.5 ± 5.2  89.2 ± 7.1 *Macaca fascicularis

Example 3: DsiRNA Inhibition of Transthyretin—Secondary Screen

96 asymmetric DsiRNAs (96 targeting Hs transthyretin, 5 of which alsotargeted Mm transthyretin) of the above experiment were then examined ina secondary assay (“Phase 2”), with results of such assays presented inhistogram form in FIGS. 3A to 3H. Specifically, the 96 asymmetricDsiRNAs selected from those tested above were assessed for inhibition ofhuman transthyretin at 1 nM, 0.1 nM and 0.03 nM in the environment ofhuman Huh7 cells (FIGS. 3A to 3D). These 96 asymmetric DsiRNAs were alsoassessed for inhibition of mouse transthyretin at 1 nM, 0.1 nM and 0.03nM in the environment of mouse AML12 cells (FIGS. 3E to 3H). As shown inFIGS. 3A to 3D, most asymmetric DsiRNAs reproducibly exhibitedsignificant human transthyretin inhibitory efficacies at sub-nanomolarconcentrations when assayed in the environment of Huh7 cells.

Without being bound by theory, it is noted that when using the RT-qPCRmethod to measure the amount of mRNA remaining after DsiRNA-mediatedmRNA knockdown, the position of the qPCR assay within the mRNA canaffect the detection of knockdown. The qPCR assay that is closer to theDsiRNA-directed mRNA cleavage point usually yields a more reliablemeasurement of mRNA level. For example, if a qPCR assay is located awayfrom the cleavage point, slow degradation of the mRNA fragment resultingfrom DsiRNA-directed cleavage can yield an artifactual high qPCR signal(a ‘false negative’ for knockdown). A sign of this is high knockdowndetected using a qPCR assay located near the DsiRNA site, andartifactual ‘low’ knockdown detected with a qPCR assay located away fromthe DsiRNA site. In this situation, the qPCR assay near the DsiRNA siteis used for quantitation. This appeared to have been the case for the3′-located TTR DsiRNAs, which showed high knockdown using the 3′-locatedqPCR assay even when the 5′-located qPCR assay recorded no or moremodest levels of TTR knockdown.

As shown in FIGS. 3E to 3H, a limited number of asymmetric DsiRNAs werealso identified to possess significant mouse transthyretin inhibitoryefficacies at sub-nanomolar concentrations when assayed in theenvironment of mouse AML12 cells.

Example 4: Assessment of Modified Forms of Transthyretin-TargetingDsiRNAs In Vitro

Twenty-four transthyretin-targeting DsiRNAs (TTR-156, TTR-157, TTR-158,TTR-187, TTR-240, TTR-241, TTR-242, TTR-243, TTR-244, TTR-245, TTR-249,TTR-252, TTR-255, TTR-257, TTR-357, TTR-657, TTR-661, TTR-754, TTR-755,TTR-756, TTR-758, TTR-895, TTR-897 and TTR-902) were prepared with2′-O-methyl guide strand modification patterns “M17”, “M35”, “M48” and“M8” as shown above. For each of these DsiRNA sequences, the passengerstrand carried the “M107” 2′-O-methyl modification patter. DsiRNAspossessing each of the four guide strand modification patterns M17, M35,M48 and M8 were assayed for transthyretin inhibition in human Huh7 cellsat 1.0 nM, 0.1 nM and 0.03 nM concentrations in the environment of theHuh7 cells. Results of these experiments are presented as histograms inFIGS. 4A-4D. In general, the 24 DsiRNA sequences exhibited a trendtowards reduced efficacy of TTR inhibition as the extent of 2′-O-methylmodification of the guide strand increased. However, for many of theDsiRNA sequences examined, a modification pattern could be identifiedthat allowed the DsiRNA to retain significant TTR inhibitory efficacy invitro. It was also notable that a number of these DsiRNAs (e.g.,TTR-156, TTR-158, TTR-255, TTR-657 and TTR-661) exhibited no apparentdecline in TTR inhibitory efficacy in even the most highly modifiedstates examined. The “false negative” effect described above for3′-terminal anti-TTR DsiRNAs was again observed. In conclusion, activemodified DsiRNA sequences were identified that possessed modificationpatterns believed to be capable of stabilizing such DsiRNAs and/orreducing immunogenicity of such DsiRNAs when therapeuticallyadministered to a subject in vivo.

Example 5: Additionally Modified Forms of Transthyretin-TargetingDsiRNAs Reduced Transthyretin In Vitro

Nine TTR-targeting DsiRNAs (TTR-156, TTR-158, TTR-240, TTR-242, TTR-244,TTR-245, TTR-255, TTR-257 and TTR-357) were prepared with both2′-O-methyl passenger strand and guide strand modification patterns. Foreach of the nine DsiRNA sequences, DsiRNAs possessing passenger strandmodification patterns selected from SM250, SM251, SM252, SM107, SM14 andSM24 (referred to as simply “M250”, “M251”, “M252”, “M107”, “M14” and“M24” in FIGS. 5A-5D, where the passenger strand modification pattern isthe first modification pattern listed, followed by the guide strandmodification pattern, e.g., “M250-M17” in FIGS. 5A-5D indicates a duplexpossessing passenger strand modification pattern “SM250” and guidestrand modification pattern “M17”) and guide strand modificationpatterns selected from M17, M35, M48 and M8 were assayed for TTRinhibition in human Huh7 cells at 1.0 nM, 0.1 nM and 0.03 nMconcentrations in the environment of the Huh7 cells. Results of theseexperiments are presented as histograms in FIGS. 5A-5D. As in Example 4above, in general, the nine DsiRNA sequences exhibited a trend towardsreduced efficacy of TTR inhibition as the extent of 2′-O-methylmodification of both passenger and guide strands increased. However, foreach of the DsiRNA sequences examined, a combination of passenger andguide strand modification patterns could be identified that allowed theDsiRNA to retain significant TTR inhibitory efficacy in vitro. Thus,such active modified DsiRNA sequences possessed modification patternsbelieved to be capable of stabilizing such DsiRNAs and/or reducingimmunogenicity of such DsiRNAs when therapeutically administered to asubject in vivo.

Example 6: Further Modified Forms of Transthyretin-Targeting DsiRNAsReduced Transthyretin In Vitro

Additional modified forms of TTR-targeting DsiRNAs were generated andtested for in vitro efficacy in Huh-7 cells. Modification patterns thatwere employed for such additional DsiRNA forms are shown in FIGS. 6A to6D and included 2′-fluoro (“2′-F”) “fill in” and tetraloop-containingformats. The fifteen distinct patterns shown in FIGS. 6A to 6D (threeforms of dNTP-tetraloop DsiRNA are shown in FIG. 6D, only differing inthe location of phosphorothioate (PS) linkages) were applied to fourtarget sequences, TTR-156, TTR-242, TTR-244 and TTR-255. Notably,TTR-156 and TTR-255 were established in the above experiments as beingparticularly tolerant of heavy 2′-O-methyl modifications. Certainmodification patterns constituted parental sequences withphosphorothioate addition, while others were 2′-F “fill ins” that eitherleft Dicer and Antisense Strand (AS) Ago2 sites unmodified or were 2′-F“fill ins” that left the Dicer site unmodified. Finally, there were“stamped on patterns” and tetraloop patterns, as show in FIGS. 6C and6D.

As demonstrated in FIGS. 7A to 7E, significant TTR knockdown activitywas observed for several highly modified forms of each TTR-targetingagent examined. Remarkably, tetraloop formats (either when comprised ofDNA or RNA residues) of such TTR-targeting agents exhibited robustlevels of TTR knockdown activity. Thus, tetraloop and otherloop-containing formats of the dsNAs of the invention are explicitlycontemplated, with exemplary tetraloop (including nicked tetraloop)structures set forth in WO 2010/033225.

As shown in FIGS. 8A to 8E, confirmatory dose-response curves wereperformed for each additional modified form of TTR-targeting DsiRNAtested. Dose-response curves for tetraloop formats of FIGS. 8A and 8Bconfirmed and extended the above finding that such formats possessrobust TTR-inhibitory activity. Meanwhile, 2′-F and phosphorothioate(PS) modified forms of TTR-244 were observed to possess high inhibitoryactivity (FIGS. 8C to 8E). Thus, additional modified forms ofTTR-targeting duplexes were identified to possess robust TTR-inhibitoryactivity.

Example 7: Assessment of In Vivo Efficacy of Transthyretin-TargetingDsiRNAs

The ability of certain, active transthyretin-targeting DsiRNAs to reducetransthyretin levels within a mouse, optionally a mouse model of liverdisease is examined. Animals are randomized and assigned to groups basedon marker levels. Dosing of animals with lipid nanoparticles (LNPs)containing DsiRNAs (optionally, an LNP formulation named EnCore-2072 isemployed) is initiated on day 0. Animals are dosed at 5 mg/kg iv, tiw×2(6 doses total). Animals are sacrificed 48 hrs after the last dose.Liver is dissected and weighed, and transthyretin levels are assessed(optionally, for a mouse model of a liver disease or disorder, theextent of reduction and/or prevention of the disease or disorder isassessed).

Example 8: Indications

The present body of knowledge in transthyretin research indicates theneed for methods to assay transthyretin activity and for compounds thatcan regulate transthyretin expression for research, diagnostic, andtherapeutic use. As described herein, the nucleic acid molecules of thepresent invention can be used in assays to diagnose disease staterelated to transthyretin levels. In addition, the nucleic acid moleculescan be used to treat disease state related to transthyretinmisregulation, levels, etc.

Particular disorders and disease states that can be associated withtransthyretin expression modulation include, but are not limited tochronic liver disease, liver inflammation, cirrhosis, liver fibrosis andhepatocellular carcinoma.

Other therapeutic agents can be combined with or used in conjunctionwith the nucleic acid molecules (e.g. DsiRNA molecules) of the instantinvention. Those skilled in the art will recognize that other compoundsand therapies used to treat the diseases and conditions described hereincan be combined with the nucleic acid molecules of the instant invention(e.g. siNA molecules) and are hence within the scope of the instantinvention. For example, for combination therapy, the nucleic acids ofthe invention can be prepared in one of at least two ways. First, theagents are physically combined in a preparation of nucleic acid andother agent, such as a mixture of a nucleic acid of the inventionencapsulated in liposomes and other agent in a solution for intravenousadministration, wherein both agents are present in a therapeuticallyeffective concentration (e.g., the other agent in solution to deliver1000-1250 mg/m2/day and liposome-associated nucleic acid of theinvention in the same solution to deliver 0.1-100 mg/kg/day).Alternatively, the agents are administered separately but simultaneouslyor successively in their respective effective doses (e.g., 1000-1250mg/m2/d other agent and 0.1 to 100 mg/kg/day nucleic acid of theinvention).

Example 9: Serum Stability for DsiRNAs

Serum stability of DsiRNA agents is assessed via incubation of DsiRNAagents in 50% fetal bovine serum for various periods of time (up to 24h) at 37° C. Serum is extracted and the nucleic acids are separated on a20% non-denaturing PAGE and can be visualized with Gelstar stain.Relative levels of protection from nuclease degradation are assessed forDsiRNAs (optionally with and without modifications).

Example 10: Diagnostic Uses

The DsiRNA molecules of the invention can be used in a variety ofdiagnostic applications, such as in the identification of moleculartargets (e.g., RNA) in a variety of applications, for example, inclinical, industrial, environmental, agricultural and/or researchsettings. Such diagnostic use of DsiRNA molecules involves utilizingreconstituted RNAi systems, for example, using cellular lysates orpartially purified cellular lysates. DsiRNA molecules of this inventioncan be used as diagnostic tools to examine genetic drift and mutationswithin diseased cells. The close relationship between DsiRNA activityand the structure of the target transthyretin RNA allows the detectionof mutations in a region of the transthyretin molecule, which alters thebase-pairing and three-dimensional structure of the target transthyretinRNA. By using multiple DsiRNA molecules described in this invention, onecan map nucleotide changes, which are important to RNA structure andfunction in vitro, as well as in cells and tissues. Cleavage of targettransthyretin RNAs with DsiRNA molecules can be used to inhibit geneexpression and define the role of specified gene products in theprogression of a transthyretin-associated disease or disorder. In thismanner, other genetic targets can be defined as important mediators ofthe disease. These experiments will lead to better treatment of thedisease progression by affording the possibility of combinationtherapies (e.g., multiple DsiRNA molecules targeted to different genes,DsiRNA molecules coupled with known small molecule inhibitors, orintermittent treatment with combinations of DsiRNA molecules and/orother chemical or biological molecules). Other in vitro uses of DsiRNAmolecules of this invention are well known in the art, and includedetection of the presence of RNAs associated with a disease or relatedcondition. Such RNA is detected by determining the presence of acleavage product after treatment with a DsiRNA using standardmethodologies, for example, fluorescence resonance emission transfer(FRET).

In a specific example, DsiRNA molecules that cleave only wild-type ormutant or polymorphic forms of the target transthyretin RNA are used forthe assay. The first DsiRNA molecules (i.e., those that cleave onlywild-type forms of target transthyretin RNA) are used to identifywild-type transthyretin RNA present in the sample and the second DsiRNAmolecules (i.e., those that cleave only mutant or polymorphic forms oftarget RNA) are used to identify mutant or polymorphic transthyretin RNAin the sample. As reaction controls, synthetic substrates of bothwild-type and mutant or polymorphic transthyretin RNA are cleaved byboth DsiRNA molecules to demonstrate the relative DsiRNA efficiencies inthe reactions and the absence of cleavage of the “non-targeted”transthyretin RNA species. The cleavage products from the syntheticsubstrates also serve to generate size markers for the analysis ofwild-type and mutant transthyretin RNAs in the sample population. Thus,each analysis requires two DsiRNA molecules, two substrates and oneunknown sample, which is combined into six reactions. The presence ofcleavage products is determined using an RNase protection assay so thatfull-length and cleavage fragments of each transthyretin RNA can beanalyzed in one lane of a polyacrylamide gel. It is not absolutelyrequired to quantify the results to gain insight into the expression ofmutant or polymorphic transthyretin RNAs and putative risk oftransthyretin-associated phenotypic changes in target cells. Theexpression of transthyretin mRNA whose protein product is implicated inthe development of the phenotype (i.e., disease related/associated) isadequate to establish risk. If probes of comparable specific activityare used for both transcripts, then a qualitative comparison oftransthyretin RNA levels is adequate and decreases the cost of theinitial diagnosis. Higher mutant or polymorphic form to wild-type ratiosare correlated with higher risk whether transthyretin RNA levels arecompared qualitatively or quantitatively.

All patents and publications mentioned in the specification areindicative of the levels of skill of those skilled in the art to whichthe invention pertains. All references cited in this disclosure areincorporated by reference to the same extent as if each reference hadbeen incorporated by reference in its entirety individually.

One skilled in the art would readily appreciate that the presentinvention is well adapted to carry out the objects and obtain the endsand advantages mentioned, as well as those inherent therein. The methodsand compositions described herein as presently representative ofpreferred embodiments are exemplary and are not intended as limitationson the scope of the invention. Changes therein and other uses will occurto those skilled in the art, which are encompassed within the spirit ofthe invention, are defined by the scope of the claims.

It will be readily apparent to one skilled in the art that varyingsubstitutions and modifications can be made to the invention disclosedherein without departing from the scope and spirit of the invention.Thus, such additional embodiments are within the scope of the presentinvention and the following claims. The present invention teaches oneskilled in the art to test various combinations and/or substitutions ofchemical modifications described herein toward generating nucleic acidconstructs with improved activity for mediating RNAi activity. Suchimproved activity can comprise improved stability, improvedbioavailability, and/or improved activation of cellular responsesmediating RNAi. Therefore, the specific embodiments described herein arenot limiting and one skilled in the art can readily appreciate thatspecific combinations of the modifications described herein can betested without undue experimentation toward identifying DsiRNA moleculeswith improved RNAi activity.

The invention illustratively described herein suitably can be practicedin the absence of any element or elements, limitation or limitationsthat are not specifically disclosed herein. Thus, for example, in eachinstance herein any of the terms “comprising”, “consisting essentiallyof”, and “consisting of” may be replaced with either of the other twoterms. The terms and expressions which have been employed are used asterms of description and not of limitation, and there is no intentionthat in the use of such terms and expressions of excluding anyequivalents of the features shown and described or portions thereof, butit is recognized that various modifications are possible within thescope of the invention claimed. Thus, it should be understood thatalthough the present invention has been specifically disclosed bypreferred embodiments, optional features, modification and variation ofthe concepts herein disclosed may be resorted to by those skilled in theart, and that such modifications and variations are considered to bewithin the scope of this invention as defined by the description and theappended claims.

In addition, where features or aspects of the invention are described interms of Markush groups or other grouping of alternatives, those skilledin the art will recognize that the invention is also thereby describedin terms of any individual member or subgroup of members of the Markushgroup or other group.

The use of the terms “a” and “an” and “the” and similar referents in thecontext of describing the invention (especially in the context of thefollowing claims) are to be construed to cover both the singular and theplural, unless otherwise indicated herein or clearly contradicted bycontext. The terms “comprising,” “having,” “including,” and “containing”are to be construed as open-ended terms (i.e., meaning “including, butnot limited to,”) unless otherwise noted. Recitation of ranges of valuesherein are merely intended to serve as a shorthand method of referringindividually to each separate value falling within the range, unlessotherwise indicated herein, and each separate value is incorporated intothe specification as if it were individually recited herein. All methodsdescribed herein can be performed in any suitable order unless otherwiseindicated herein or otherwise clearly contradicted by context. The useof any and all examples, or exemplary language (e.g., “such as”)provided herein, is intended merely to better illuminate the inventionand does not pose a limitation on the scope of the invention unlessotherwise claimed. No language in the specification should be construedas indicating any non-claimed element as essential to the practice ofthe invention.

Embodiments of this invention are described herein, including the bestmode known to the inventors for carrying out the invention. Variationsof those embodiments may become apparent to those of ordinary skill inthe art upon reading the foregoing description.

The inventors expect skilled artisans to employ such variations asappropriate, and the inventors intend for the invention to be practicedotherwise than as specifically described herein. Accordingly, thisinvention includes all modifications and equivalents of the subjectmatter recited in the claims appended hereto as permitted by applicablelaw. Moreover, any combination of the above-described elements in allpossible variations thereof is encompassed by the invention unlessotherwise indicated herein or otherwise clearly contradicted by context.Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, many equivalents to the specificembodiments of the invention described herein. Such equivalents areintended to be encompassed by the following claims.

We claim:
 1. A double stranded nucleic acid (dsNA) comprising first andsecond oligonucleotide strands, wherein the first strand is 15-66nucleotides in length and the second strand is 20-66 nucleotides inlength, wherein the second oligonucleotide strand has a region ofcomplementary to a target transthyretin mRNA sequence selected from SEQID NOs: 2052, 2054, 2060, 2062, 2064, 2066, 2068, 2084, 2085, and 2087and is capable of reducing expression of transthyretin mRNA containingthe target mRNA sequence when the dsNA is introduced into a mammaliancell, wherein the second oligonucleotide strand comprises a sequenceselected from the group consisting of SEQ ID NOs: 516, 518, 524, 526,528, 530, 532, 548, 549 and 551, and wherein the dsNA comprises RNA andhas at least one modified nucleotide.
 2. The dsNA of claim 1, whereinthe second oligonucleotide strand forms a duplex region of 19-21 basepairs or 21-25 base pairs in length with the first oligonucleotidestrand.
 3. The dsNA of claim 1, wherein the second oligonucleotidestrand forms a duplex region of at least 25 base pairs in length withthe first oligonucleotide strand.
 4. The dsNA of claim 2, wherein thesecond oligonucleotide strand has a 3′-overhang of 2 nucleotides whenthe second oligonucleotide forms a duplex region with the firstoligonucleotide strand.
 5. The dsNA of claim 1, wherein the 3′ end ofthe first oligonucleotide strand and the 5′ end of the secondoligonucleotide strand are joined by a polynucleotide sequencecomprising ribonucleotides, deoxyribonucleotides or both, optionallywherein the polynucleotide sequence comprises a tetraloop sequence. 6.The dsNA of claim 1, wherein the modified nucleotide is selected fromthe group consisting of 2′-O-methyl, 2′-methoxyethoxy, 2′-fluoro,2′-allyl, 2′-O-[2-(methylamino)-2-oxoethyl], 4′-thio,4′-CH₂—O-2′-bridge, 4′-(CH₂)₂—O-2′-bridge, 2′-LNA, 2′-amino and2′-O—(N-methlycarbamate).
 7. The dsNA of claim 1, wherein the modifiednucleotide is selected from the group consisting of adeoxyribonucleotide, a dideoxyribonucleotide, an acyclonucleotide, a3′-deoxyadenosine (cordycepin), a 3′-azido-3′-deoxythymidine (AZT), a2′,3′-dideoxyinosine (ddI), a 2′,3′-dideoxy-3′-thiacytidine (3TC), a2′,3′-didehydro-2′,3′-dideoxythymidine (d4T), a monophosphate nucleotideof 3′-azido-3′-deoxythymidine (AZT), a 2′,3′-dideoxy-3′-thiacytidine(3TC) and a monophosphate nucleotide of2′,3′-didehydro-2′,3′-dideoxythymidine (d4T), a 4-thiouracil, a5-bromouracil, a 5-iodouracil, a 5-(3-aminoallyl)-uracil, a 2′-O-alkylribonucleotide, a 2′-O-methyl ribonucleotide, a 2′-amino ribonucleotide,a 2′-fluoro ribonucleotide, and a locked nucleic acid.
 8. The dsNA ofclaim 1, comprising a phosphate backbone modification selected from thegroup consisting of a phosphonate, a phosphorothioate and aphosphotriester.
 9. The dsNA of claim 1, wherein the dsNA is attached toa targeting ligand selected from the group consisting of a GalNAcmoiety, a cholesterol, and a cholesterol targeting ligand.
 10. The dsNAof claim 1, wherein the first oligonucleotide strand comprises asequence selected from the group consisting of SEQ ID Nos: 132, 134,140, 142, 144, 146, 148, 164, 165, and
 167. 11. The dsNA of claim 1,wherein the first and second oligonucleotides comprise a pair ofmodified oligonucleotides defined by a TTR # and corresponding sequencesselected from TTR-422, SEQ ID NO: 132 and SEQ ID NO:516; TTR-424, SEQ IDNO: 134 and SEQ ID NO: 518; TTR-430, SEQ ID NO: 140 and SEQ ID NO: 524:TTR-432, SEQ ID NO: 142 and SEQ ID NO: 526; TTR-434, SEQ ID NO: 144 andSEQ ID NO: 528; TTR-436, SEQ ID NO: 146 and SEQ ID NO: 530; TTR-439, SEQID NO: 148 and SEQ ID NO: 532; TTR-483, SEQ ID NO: 164 and SEQ ID NO:548; TTR-484, SEQ ID NO: 165 and SEQ ID NO: 549; and TTR-489, SEQ ID NO:1667 and SEQ ID NO:
 551. 12. A pharmaceutical composition comprising thedsNA of claim 1, and a pharmaceutically acceptable carrier.
 13. A methodfor reducing expression of a target transthyretin mRNA in a mammal,comprising administering a dsNA of claim 1 to a mammal in an amountsufficient to reduce expression of a target transthyretin mRNA in themammal.
 14. A method for treating or preventing atransthyretin-associated disease or disorder in a patient, comprisingadministering to the patient in need thereof an amount of a dsNA ofclaim 1 effective to treat or prevent the disease or disorder in thepatient.
 15. The method of claim 14, wherein the disease or disorder isamyloidosis.